Cycloalkyl alkanoic acids as integrin receptor antagonists

ABSTRACT

The present invention relates to a class of compounds represented by the Formula I 
                 
 
Wherein A 1  is a pyridinyl of the formula 
                 
 
optionally substituted by one or more R k  selected from the group consisting of hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl, haloalkyl, cyano, amino alkylamino, halogen, acylamino, sulfonamide and —COR; and R is hydroxy, alkoxy, alkyl or amino; and pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising compounds of the Formula I, and methods of selectively inhibiting or antagonizing the α v β 3  and/or α v β 5  integrin.

The present application claims priority under Title 35, United StatesCode, §119 of U.S. Provisional application Ser. No. 60/211,781 filedJun. 15, 2000.

FIELD OF THE INVENTION

The present invention relates to pharmaceutical agents (compounds) whichare α_(V)β₃ and/or α_(V)β₅ integrin antagonists and as such are usefulin pharmaceutical compositions and in methods for treating conditionsmediated by α_(V)β₃ and/or α_(V)β₅ integrins.

BACKGROUND OF THE INVENTION

The integrin α_(V)β₃ (also known as vitronectin receptor), is a memberof the integrin family of heterodimeric transmembrane glycoproteincomplexes that mediate cellular adhesion events and signal transductionprocesses. Integrin α_(V)β₃ is expressed in number of cell types and hasbeen shown to mediate several biologically relevant processes, includingadhesion of osteoclasts to the bone matrix, vascular smooth muscle cellmigration and angiogenesis.

The integrin α_(V)β₃ has been shown to play a role in various conditionsor disease states including tumor metastasis, solid tumor growth(neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia ofmalignancy, osteopenia, angiogenesis, including tumor angiogenesis andlymphangiogenesis, retinopathy including macular degeneration,arthritis, including rheumatoid arthritis, periodontal disease,psoriasis and smooth muscle cell migration (e.g. restenosisartherosclerosis). The compounds of the present invention are α_(V)β₃antagonists and can be used, alone or in combination with othertherapeutic agents, in the treatment or modulation of various conditionsor disease states described above. Additionally, it has been found thatsuch agents would be useful as antivirals, antifungals andantimicrobials.

The integrin α_(V)β₅ is thought to play a role in neovascularization. M.C. Friedlander, et al., Science, 270, 1500-1502 (1995) disclose that amonoclonal antibody for α_(V)β₅ inhibits VEFG-induced angiogenesis inthe rabbit cornea and the chick chorioallantoic membrane model.Therefore compounds which act as antagonists of the α_(V)β₅ integrinwill inhibit neovascularization and will be useful for treating andpreventing angiogenesis metastasis, tumor growth, macular degenerationand diabetic retionopathy.

Certain compounds may antagonize both the α_(V)β₅ and the α_(V)β₃receptor and therefore are referred to as “mixed α_(V)β₅/α_(V)β₃antagonists” or “dual α_(V)β₃/α_(V)β₅ antagonists”. Such dual or mixedantagonists are useful for treating or preventing angiogenesis, tumormetastasis, tumor growth, diabetic retinopathy, macular degeneration,atherosclerosis and osteoporosis.

It has been shown that the α_(V)β₃ integrin and other α_(V) containingintegrins bind to a number of Arg-Gly-Asp (RGD) containing matrixmacromolecules. Compounds containing the RGD sequence mimicextracellular matrix ligands so as to bind to cell surface receptors.However, it is also known that RGD peptides in general are non-selectivefor RGD dependent integrins. For example, most RGD peptides which bindto α_(V)β₃ also bind to α_(V)β₅, α_(V)β₁ and α_(IIb)β₃. Antagonism ofplatelet α_(IIb)β₃ (also known as the fibrinogen receptor) is known toblock platelet aggregation in humans. In order to avoid bleedingside-effects when treating the conditions or disease states associatedwith the integrin α_(V)β₃, it would be beneficial to develop compoundswhich are selective antagonists of α_(V)β₃ as opposed to α_(IIb)β₃.

Tumor cell invasion occurs by a three step process: 1) tumor cellattachment to extracellular matrix; 2) proteolytic dissolution of thematrix; and 3) movement of the cells through the dissolved barrier. Thisprocess can occur repeatedly and can result in metastases at sitesdistant from the original tumor.

Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561)have shown that the α_(V)β₃ integrin has a biological function inmelanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA,Vol. 91 (1994) 8856-60) have demonstrated that the integrin α_(V)β₃expressed on human melanoma cells promotes a survival signal, protectingthe cells from apoptosis. Mediation of the tumor cell metastatic pathwayby interference with the α_(V)β₃ integrin cell adhesion receptor toimpede tumor metastasis would be beneficial.

Further, with the discovery that α_(V)β₃ plays a role in the process oflymphatic dissemination via adhesion of melanoma cells to lymph node bybinding the vitronectin receptor (Nip et al, J Clin Invest 1992,90,1406), inhibitors of α_(V)β₃ may also be useful for makingalterations in lymphatic endothelial-tumorcell adhesion, thereby furtherreducing the potential for tumor metastasis.

Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated thatantagonists of α_(V)β₃ provide a therapeutic approach for the treatmentof neoplasia (inhibition of solid tumor growth) since systemicadministration of α_(V)β₃ antagonists causes dramatic regression ofvarious histologically distinct human tumors.

The compounds of the present invention are useful for the treatment,including prevention of angiogenic disorders. The term angiogenicdisorders include conditions involving abnormal neovascularization. Thegrowth of new blood vessels, or angiogenesis, also contributes topathological conditions such as diabetic retinopathy including maculardegeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994)445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol.175, (1992), 1135-1138). Therefore, α_(V)β₃ antagonists would be usefultherapeutic agents for treating such conditions associated withneovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).

It has been reported that the cell surface receptor α_(V)β₃ is the majorintegrin on osteoclasts responsible for attachment to bone (for areview, see Rodan and Rodan, 1997, J. Endocrinol. 154, S47, Nakamura etal., J. Cell Science, 1999 112, 3985). Osteoclasts cause bone resorptionand when such bone resorbing activity exceeds bone forming activity itleads to an increased number of bone fractures, incapacitation andincreased mortality. Antagonists of α_(V)β₃ have been shown to be potentinhibitors of osteoclastic activity both in vitro (Sato et al., J. Cell.Biol., Vol. 111 (1990) 1713-1723) and in vivo (Fisher et al.,Endocrinology, Vol. 132 (1993) 1411-1413). Antagonism of α_(V)β₃ leadsto decreased bone resorption and therefore restores a normal balance ofbone forming and resorbing activity. Thus it would be beneficial toprovide antagonists of osteoclast α_(V)β₃ which are effective inhibitorsof bone resorption and therefore are useful in the treatment orprevention of osteoporosis.

The role of the α_(V)β₃ integrin in smooth muscle cell migration alsomakes it a therapeutic target for prevention or inhibition of neointimalhyperplasia which is a leading cause of restenosis after vascularprocedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34).Prevention or inhibition of neointimal hyperplasia by pharmaceuticalagents to prevent or inhibit restenosis would be beneficial.

White (Current Biology, Vol. 3(9)(1993) 596-599) has reported thatadenovirus uses α_(V)β₃ for entering host cells. The integrin appears tobe required for endocytosis of the virus particle and may be requiredfor penetration of the viral genome into the host cell cytoplasm. Thuscompounds which inhibit α_(V)β₃ would find usefulness as antiviralagents.

SUMMARY OF THE INVENTION

The compounds of this invention are 1) α_(V)β₃ integrin antagonists; or2) α_(V)β₅ integrin antagonists; or 3) mixed or dual α_(V)β₃/α_(V)β₅antagonists. The present invention includes compounds which inhibit therespective integrins and also includes pharmaceutical compositionscomprising such compounds. The present invention further provides formethods for treating or preventing conditions mediated by the α_(V)β₃and/or α_(V)β₅ receptors in a mammal in need of such treatmentcomprising administering a therapeutically effective amount of thecompounds of the present invention and pharmaceutical compositions ofthe present invention. Administration of such compounds and compositionsof the present invention inhibits angiogenesis, tumor metastasis, tumorgrowth, osteoporosis, Paget's disease, humoral hypercalcemia ofmalignancy, retinopathy, macular degeneration, arthritis, periodontaldisease, smooth muscle cell migration, including restenosis andartherosclerosis, and viral diseases.

Further, it has been found that the selective antagonism of the α_(V)β₃integrin is desirable in that the α_(V)β₆ integrin may play a role innormal physiological processes of tissue repair and cellular turnoverthat routinely occur in the skin and pulmonary tissue, and α_(V)β₈ mayplay a role in the regulation of growth in the human pathway. Therefore,compounds which selectively inihibit the α_(V)β₃ integrin as opposed tothe α_(V)β₆ and/or the α_(V)β₈ integrin have reduced side-effectsassociated with inhibtion of the α_(V)β₆ and/or the α_(V)β₈ integrin. Itis therefore another object of the present invention to providecompounds that are selective antagonists of α_(V)β₃ and/or α_(V)β₅ asopposed to α_(V)β₆, and it is yet another object of the presentinvention to provide compounds that are selective antagonists of α_(V)β₃and/or α_(V)β₅ as opposed to α_(V)β₈.

The present invention relates to a class of compounds represented by theFormula I

or a pharmaceutically acceptable salt thereof, wherein

is a 4-8 membered monocyclic ring or a 7-12 membered bicyclic ring,which ring is optionally saturated or unsaturated; which ring isoptionally substituted with one or more substituent selected from thegroup consisting of alkyl, haloalkyl, aryl, heteroaryl, halogen,alkoxyalkyl, aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl,thioalkyl, amino, alkylamino, arylamino, alkylsulfonamide, acyl,acylamino, alkylsulfone, sulfonamide, allyl, alkenyl, methylenedioxy,ethylenedioxy, alkynyl, carboxamide, cyano, and —(CH₂)_(n) COR wherein nis 0-2 and R is hydroxy, alkoxy, alkyl or amino;

-   -   A¹ is a 5-9 membered monocyclic ring or 7-12 membered bicyclic        heterocycle ring of the formula    -    containing at least one nitrogen atom and optionally containing        1 to 4 heteroatoms, selected from the group consisting of O, N,        S, SO₂ and CO; optionally saturated or unsaturated; optionally        substituted by one or more R^(k) is selected from the group        consisting of hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl,        cyano, amino, alkylamino, haloalkyl, halogen, acylamino,        sulfonamide and —COR wherein R is hydroxy, alkoxy, alkyl or        amino;        or A¹ is    -   wherein Y¹ is selected from the group consisting of N—R², O, and        S;    -   R² is selected from the group consisting of H; alkyl; aryl;        hydroxy; alkoxy; cyano; amido; alkylcarbonyl; arylcarbonyl;        alkoxycarbonyl; aryloxycarbonyl; haloalkylcarbonyl;        haloalkoxycarbonyl; alkylthiocarbonyl; arylthiocarbonyl;        acyloxymethoxycarbonyl;    -   R² taken together with R⁷ forms a 4-12 membered dinitrogen        containing heterocycle optionally substituted with one or more        substituent selected from the group consisting of lower alkyl,        thioalkyl, alkylamino, hydroxy, keto, alkoxy, halo, phenyl,        amino, carboxyl or carboxyl ester;        or R² taken together with R⁷ forms a 4-12 membered heterocycle        containing one or more heteroatom selected from O, N and S        optionally unsaturated;        or R² taken together with R⁷ forms a 5 membered heteroaromatic        ring fused with a aryl or heteroaryl ring;    -   R⁷ (when not taken together with R²) and R⁸ are independently        selected from the group consisting of H; alkyl; aralkyl; amino;        alkylamino; hydroxy; alkoxy; arylamino; amido, alkylcarbonyl,        arylcarbonyl; alkoxycarbonyl; aryloxy; aryloxycarbonyl;        haloalkylcarbonyl; haloalkoxycarbonyl; alkylthiocarbonyl;        arylthiocarbonyl; acyloxymethoxycarbonyl; cycloalkyl;        bicycloalkyl; aryl; acyl; benzoyl;        or NR⁷ and R⁸ taken together form a 4-12 membered mononitrogen        containing monocyclic or bicyclic ring optionally substituted        with one or more substituent selected from lower alkyl, carboxyl        derivatives, aryl or hydroxy and wherein said ring optionally        contains a heteroatom selected from the group consisting of O, N        and S; R⁵ is selected from the group consisting of H, and alkyl;        or        A is    -   wherein Y is selected from the group consisting of alkyl;        cycloalkyl; bicycloalkyl; aryl; monocyclic heterocycles;    -   Z₁ is selected from the group consisting of CH₂, CH₂O, O, NH,        NR_(k), CO, S, SO, CH(OH), and SO₂, wherein R_(k) is selected        from H or lower alkyl;    -   Z₂ is a 1-5 carbon linker optionally containing one or more        heteroatom selected from the group consisting of O, S and N;        alternatively Z₁-Z₂ may further contain a carboxamide, sulfone,        oxime, sulfonamide, alkenyl, alkynyl, or acyl group;    -   wherein the carbon and nitrogen atoms of Z₁-Z₂ are optionally        substituted by alkyl, alkoxy, thioalkyl, alkylsulfone, aryl,        alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl,        carboxyalkyl, halogen, haloalkyl or acylamino;    -   wherein Z₂-Z₁ is attached to        at the para or meta position relative to the X₁ substituent;    -   n is an integer 0, 1 or 2;    -   R^(c) is selected from the group consisting of hydrogen; alkyl;        halogen, hydroxy, nitro, alkoxy, amino, haloalkyl, aryl,        heteroaryl, alkoxyalkyl, aminoalkyl, hydroxyalkyl, thioalkyl,        alkylamino, arylamino, alkylsulfonylamino, acyl, acylamino,        sulfonyl, sulfonamide, allyl, alkenyl, methylenedioxy,        ethylenedioxy, alkynyl, alkynylalkyl, carboxy, alkoxycarbonyl,        carboxamido, cyano, and —(CH₂)_(n)—COR wherein n is 0-2 and R is        selected from hydroxy, alkoxy, alkyl and amino;    -   X₁ is selected from the group consisting of —O—, CO, SO₂, NR^(m)        and (CHR^(p))_(q); wherein R^(m) is H or alkyl; R^(p) is H,        alkyl, alkoxy or hydroxy and q is 0 or 1;    -   X₂ is selected from the group consisting of —CHR^(e)—, CO, SO₂,        O, NR^(f) and S;    -   R^(e) is selected from the group consisting of H, alkyl, hydroxy        and alkoxy; R^(f) is H or alkyl;    -   X or Y are independently selected from the group consisting of        —CR^(g)— or —N— wherein R^(g) is selected from the group        consisting of H, alkyl, haloalkyl, fluoro, alkoxyalkyl, alkynyl,        aryl, heteroaryl, aralkyl, alkylsulfone, heteroaralkyl, hydroxy,        alkoxy, hydroxyalkyl, and carboxyalkyl;

The group X—X₂—Y optionally contains a moiety selected from the groupconsisting of acyl, alkyl, amino, ether, thioether, sulfone, and olefin;

forms a 3-8 membered monocyclic ring system; or an 8-11 memberedbicyclic system; optionally saturated or unsaturated; the monocyclicring system optionally containing 1-2 heteroatoms selected from N, O andS; the bicyclic ring system optionally containing 1-4 heteroatomsselected from N, O, S or optionally containing the group such as SO₂ orCO); and optionally substituted with one or more substituent selectedfrom the group consisting of alkyl, halogen, cyano, carboalkoxy,haloalkyl, alkoxyalkyl, alkylsulfone, aryl, heteroaryl, aralkyl,heteroaralkyl or alkoxy;

-   -   R^(b) is X₃-R^(h) wherein X₃ is selected from the group        consisting of O, S and NR^(j) wherein R^(h) and R^(j) are        independently selected from the group consisting of H, alkyl,        acyl, aryl, aralkyl and alkoxyalkyl; and    -   and ni s 0, 1 or 2.

It is another object of the invention to provide pharmaceuticalcompositions comprising compounds of the Formula I. Such compounds andcompositions are useful in selectively inhibiting or antagonizing theα_(V)β₃ and/or α_(V)β₅ integrin(s) and therefore in another embodimentthe present invention relates to a method of selectively inhibiting orantagonizing the α_(V)β₃ and/or α_(V)β₅ integrin(s). The inventionfurther involves treating or inhibiting pathological conditionsassociated therewith such as osteoporosis, humoral hypercalcemia ofmalignancy, Paget's disease, tumor metastasis, solid tumor growth(neoplasia), angiogenesis, including tumor angiogenesis, retinopathyincluding macular degeneration and diabetic retinopathy, arthritis,including rheumatoid arthritis, periodontal disease, psoriasis, smoothmuscle cell migration including restenosis or atherosclerosis in amammal in need of such treatment. Additionally, such pharmaceuticalagents are useful as antiviral agents, antifungals and antimicrobials.The compounds of the present invention may be used alone or incombination with other pharmaceutical agents.

DETAILED DESCRIPTION

The present invention relates to a class of compounds represented by theFormula I, described above.

In another embodiment of the present invention

is aryl or fused aryl optionally substituted by one or more substituentselected from lower alkyl, halogen, alkoxy, hydroxy, cyano, amino,alkylamino, dialkylamino or methylsulfonamide.

Another embodiments of

include the following heterocyclic ring systems containing at least onenitrogen atom:

wherein R¹ is H, alkyl, alkoxyalkyl, acyl, hydroxyalkyl, haloalkyl, oralkoxycarbonyl; and Z is H, alkyl, alkoxy, hydroxy, amino, alkylamino,carboxyl, alkoxycarbonyl, hydroxyalkyl, halogen or haloalkyl.

More specifically another embodiments include pyridylamino,imidazolylamino, oxazolylamino, thiazolylamino, pyrimidinylamino,quinoline, isoquinoline, morpholinopyridine, tetrahydronaphthyridine,tetrahydroquinoline, imidazopyridine, benzimidazole, pyridone orquinolone.

The following heteroaryls include the ring systems as described above.

For the pyridyl derived heterocycle, the substituents X₄ and X₅ arepreferentially H, alkyl, branched alkyl, alkylamino, alkoxyalkylamino,haloalkyl, thioalkyl, halogen, amino, alkoxy, aryloxy, alkoxyalkyl,hydroxy, cyano or acylamino groups. In another embodiment of theinvention, the substituents X₄ and X₅ can be methyl, methoxy, amine,methylamine, dimethylamine, hydroxy, chloro, bromo, fluoro,trifluoromethyl and cyano. X₆ may preferentially be H, alkyl, halogen(F, Cl) alkoxy or haloalkyl. Alternately, the pyridyl ring can be fusedwith a 4-8 membered ring, optionally saturated or unsaturated. Someexamples of these ring systems include quinoline, azaquinoline,tetrahydroquinoline, imidazopyridine and the like. The monocyclic ringsystems such as imidazole, thiazole, oxazole, and the like, may containan amino or alkylamino substituent at any position within the ring.

In another embodiment of the present invention, when Z₁ of Formula 1 isCO or SO₂, the linkage A¹-Z₂ of Formula I preferentially includes thefollowing heterocycle derived ring systems: pyridine, imidazole,thiazole, oxazole, benzimidazole, imidazopyridine and the like.

Other preferred heterocycles formed by the A₁-Z₂ moiety of the presentinvention include

The substituent RC is preferably alkyl, halogen, alkoxy, hydroxy, cyano,a carboxyl derivative or methyl sulfonamide.

The invention further relates to pharmaceutical compositions containingtherapeutically effective amounts of the compounds of Formula I.

The invention also relates to a method of selectively inhibiting orantagonizing the α_(V)β₃ integrin and/or the α_(V)β₅ integrin and morespecifically relates to a method of inhibiting bone resorption,periodontal disease, osteoporosis, humoral hypercalcemia of malignancy,Paget's disease, tumor metastasis, solid tumor growth (neoplasia),angiogenesis, including tumor angiogenesis, retinopathy includingmacular degeneration and diabetic retinopathy, arthritis, includingrheumatoid arthritis, smooth muscle cell migration, including restenosisand atherosclerosis by administering a therapeutically effective amountof a compound of the Formula I to achieve such inhibition together witha pharmaceutically acceptable carrier.

The following is a list of definitions of various terms used herein:

As used herein, the terms “alkyl” or “lower alkyl” refer to a straightchain or branched chain hydrocarbon radicals having from about 1 toabout 10 carbon atoms, and more preferably 1 to about 6 carbon atoms.Examples of such alkyl radicals are methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, hexyl,isohexyl, and the like.

As used herein the terms “alkenyl” or “lower alkenyl” refer tounsaturated acyclic hydrocarbon radicals containing at least one doublebond and 2 to about 6 carbon atoms, which carbon—carbon double bond mayhave either cis or trans geometry within the alkenyl moiety, relative togroups substituted on the double bond carbons. Examples of such groupsare ethenyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl and thelike.

As used herein the terms “alkynyl” or “lower alkynyl” refer to acyclichydrocarbon radicals containing one or more triple bonds and 2 to about6 carbon atoms. Examples of such groups are ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

The term “cycloalkyl” as used herein means saturated or partiallyunsaturated cyclic carbon radicals containing 3 to about 8 carbon atomsand more preferably 4 to about 6 carbon atoms. Examples of suchcycloalkyl radicals include cyclopropyl, cyclopropenyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-cyclohexen-1-yl, and the like.

The term “aryl” as used herein denotes aromatic ring systems composed ofone or more aromatic rings. Preferred aryl groups are those consistingof one, two or three aromatic rings. The term embraces aromatic radicalssuch as phenyl, pyridyl, naphthyl, thiophene, furan, biphenyl and thelike.

As used herein, the term “cyano” is represented by a radical of theformula 2

The terms “hydroxy” and “hydroxyl” as used herein are synonymous and arerepresented by a radical of the formula 3

The term “lower alkylene” or “alkylene” as used herein refers todivalent linear or branched saturated hydrocarbon radicals of 1 to about6 carbon atoms.

As used herein the term “alkoxy” refers to straight or branched chainoxy containing radicals of the formula —OR²⁰, wherein R²⁰ is an alkylgroup as defined above. Examples of alkoxy groups encompassed includemethoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, isobutoxy, sec-butoxy,t-butoxy and the like.

As used herein the terms “arylalkyl” or “aralkyl” refer to a radical of

the formula4 wherein R²¹ is aryl as defined above and R²² is an alkyleneas defined above. Examples of aralkyl groups include benzyl,pyridylmethyl, naphthylpropyl, phenethyl and the like.

As used herein the term “nitro” is represented by a radical of theformula 5

As used herein the term “halo” or “halogen” refers to bromo, chloro,fluoro or iodo.

As used herein the term “haloalkyl” refers to alkyl groups as definedabove substituted with one or more of the same or different halo groupsat one or more carbon atom. Examples of haloalkyl groups includetrifluoromethyl, dichloroethyl, fluoropropyl and the like.

As used herein the term “carboxyl” or “carboxy” refers to a radical ofthe formula —COOH.

As used herein the term “carboxyl ester” refers to a radical of theformula —COOR²³ wherein R²³ is selected from the group consisting of H,alkyl, aralkyl or aryl as defined above.

As used herein the term “carboxyl derivative” refers to a radical of theformula

6 wherein Y⁶ and Y⁷ are independently selected from the group consistingof O, N or S and R²³ is selected from the group consisting of H, alkyl,aralkyl or aryl as defined above.

As used herein the term “amino” is represented by a radical of theformula —NH₂.

As used herein the term “alkylsulfonyl” or “alkylsulfone” refers to aradical of the

formula7 wherein R²⁴ is alkyl as defined above.

As used herein the term “alkylthio” refers to a radical of the formula—SR²⁴ wherein R is alkyl as defined above.

As used herein the term “sulfonic acid” refers to a radical of the

formula8 wherein R²⁵ is alkyl as defined above.

As used herein the term “sulfonamide” or “sulfonamido” refers to aradical of the

formula 9 wherein R⁷ and R⁸ are as defined above.

As used herein the term “fused aryl” refers to an aromatic ring such asthe aryl groups defined above fused to one or more phenyl rings.Embraced by the term “fused aryl” is the radical naphthyl and the like.

As used herein the terms “monocyclic heterocycle” or “monocyclicheterocyclic” refer to a monocyclic ring containing from 4 to about 12atoms, and more preferably from 5 to about 10 atoms, wherein 1 to 3 ofthe atoms are heteroatoms selected from the group consisting of oxygen,nitrogen and sulfur with the understanding that if two or more differentheteroatoms are present at least one of the heteroatoms must benitrogen. Representative of such monocyclic heterocycles are imidazole,furan, pyridine, oxazole, pyran, triazole, thiophene, pyrazole,thiazole, thiadiazole, and the like.

As used herein the term “fused monocyclic heterocycle” refers to amonocyclic heterocycle as defined above with a benzene fused thereto.Examples of such fused monocyclic heterocycles include benzofuran,benzopyran, benzodioxole, benzothiazole, benzothiophene, benzimidazoleand the like.

As used herein the term “methylenedioxy” refers to the

radical and the term “ethylenedioxy” refers to the radical

1011 As used herein the term “4-12 membered dinitrogen containingheterocycle refers to a radical of the formula

12 wherein m is an integer 1 to 1 and R¹⁹ is H, alkyl, aryl, or aralkyland more preferably refers to 4-9 membered ring and includes rings suchas imidazoline.

As used herein the term “5-membered optionally substitutedheteroaromatic ring” includes for example a radical of the formula

and “5-membered heteroaromatic ring fused with a phenyl” refers to sucha “5-membered heteroaromatic ring” with a phenyl fused thereto.Representative of such 5-membered heteroaromatic rings fused with aphenyl is benzimidazole.

As used herein the term “bicycloalkyl” refers to a bicyclic hydrocarbonradical containing 6 to about 12 carbon atoms which is saturated orpartially unsaturated.

As used herein the term “acyl” refers to a radical of the formula 13

wherein R²⁶ is alkyl, alkenyl, alkynyl, aryl or aralkyl and optionallysubstituted thereon as defined above. Encompassed by such radical arethe groups acetyl, benzoyl and the like.

As used herein the term “thio” refers to a radical of the formula 14

As used herein the term “sulfonyl” refers to a radical of the formula 15

wherein R²⁷ is alkyl, aryl or aralkyl as defined above.

As used herein the term “haloalkylthio” refers to a radical of theformula —S—R²⁸ wherein R²⁸ is haloalkyl as defined above.

As used herein the term “aryloxy” refers to a radical of the formula 16

wherein R²⁹ is aryl as defined above.

As used herein the term “acylamino” refers to a radical of the formula

wherein R³⁰ is alkyl, aralkyl or aryl as defined above.

As used herein the term “amido” refers to a radical of the formula 17

As used herein the term “alkylamino” refers to a radical of the formula—NHR³² wherein R³² is alkyl as defined above.

As used herein the term “dialkylamino” refers to a radical of theformula —NR³³R³⁴ wherein R³³ and R³⁴ are the same or different alkylgroups as defined above.

As used herein the term “trifluoromethyl” refers to a radical of theformula 18

As used herein the term “trifluoroalkoxy” refers to a radical of theformula 19

wherein R³⁵ is a bond or an alkylene as defined above.

As used herein the term “alkylaminosulfonyl” or “alkylsulfonamide” referto a radical of the formula 20

wherein R³⁶ is alkyl as defined above.

As used herein the term “alkylsulfonylamino” refers to a radical of theformula 21

wherein R³⁶ is alkyl as defined above.

As used herein the term “trifluoromethylthio” refers to a radical of theformula 22

As used herein the term “trifluoromethylsulfonyl” refers to a radical ofthe formula 23

As used herein the term “4-12 membered mono-nitrogen containingmonocyclic or bicyclic ring” refers to a saturated or partiallyunsaturated monocyclic or bicyclic ring of 4-12 atoms and morepreferably a ring of 4-9 atoms wherein one atom is nitrogen. Such ringsmay optionally contain additional heteroatoms selected from nitrogen,oxygen or sulfur. Included within this group are morpholine, piperidine,piperazine, thiomorpholine, pyrrolidine, proline, azacycloheptene andthe like.

As used herein the term “benzyl” refers to the radical

As used herein the term “phenethyl” refers to the radical

As used herein the term “4-12 membered mono-nitrogen containingmonosulfur or monooxygen containing heterocyclic ring” refers to a ringconsisting of 4 to 12 atoms and more preferably 4 to 9 atoms wherein atleast one atom is a nitrogen and at least one atom is oxygen or sulfur.Encompassed within this definition are rings such as thiazoline and thelike.

As used herein the term “alkylcarbonyl” refers to a radical of theformula 26

wherein R⁵⁰ is alkyl as defined above.

As used herein the term “arylcarbonyl” refers to a radical of theformula 27

wherein R⁵⁰ is aryl as defined above.

As used herein the term “alkoxycarbonyl” refers to a radical of theformula 28

wherein R⁵² is alkoxy as defined above.

As used herein the term “aryloxycarbonyl” refers to a radical of theformula 29

wherein R⁵¹ is aryl as defined above.

As used herein the term “haloalkylcarbonyl” refers to a radical of theformula 30

wherein R⁵³ is haloalkyl as defined above.

As used herein the term “haloalkoxycarbonyl” refers to a radical of theformula 31

wherein R⁵³ is haloalkyl as defined above.

As used herein the term “alkylthiocarbonyl” refers to a radical of theformula 32

wherein R⁵⁰ is alkyl as defined above.

As used herein the term “arylthiocarbonyl” refers to a radical of theformula 33

wherein R⁵¹ is aryl as defined above.

As used herein the term “acyloxymethoxycarbonyl” refers to a radical ofthe formula 34

wherein R⁵⁴ is acyl as defined above.

As used herein the term “arylamino” refers to a radical of the formulaR⁵¹—NH— wherein R⁵¹ is aryl as defined above.

As used herein the term “alkylamido” refers to a radical of the formula35

wherein R⁵⁰ is alkyl as defined above.

As used herein the term “N,N-dialkylamido” refers to a radical of theformula 36

wherein R⁵⁰ is the same or different alkyl group as defined above.

As used herein the term “acyloxy” refers to a radical of the formulaR⁵⁵—O— wherein R⁵⁵ is acyl as defined above.

As used herein the term “alkenylene” refers to a linear hydrocarbonradical of 1 to about 8 carbon atoms containing at least one doublebond.

As used herein the term “alkoxyalkyl” refers to a radical of the formula

wherein R⁵⁶ is alkoxy as defined above and R⁵⁷ is alkylene as definedabove.

As used herein the term “alkynylalkyl” refers to a radical of theformula R⁵⁹—R⁶⁰— wherein R⁵⁹ is alkynyl as defined as above and R⁶⁰ isalkylene as defined as above.

As used herein the term “alkynylene” refers to divalent alkynyl radicalsof 1 to about 6 carbon atoms.

As used herein the term “allyl” refers of a radical of the formula—CH₂CH═CH₂.

As used herein the term “aminoalkyl” refers to a radical of the formulaH₂N—R⁶¹ wherein R⁶¹ is alkylene as defined above.

As used herein the term “benzoyl” refers to the aryl radical C₆H₅—CO—.

As used herein the terms “carboxamide” or “carboxamido” refer to aradical of the formula —CO—NH₂.

As used herein the term “carboxyalkyl” refers to a radical HOOC—R⁶²—wherein R⁶² is alkylene as defined as above.

As used herein the term “carboxylic acid” refers to the radical —COOH Asused herein the term “ether” refers to a radical of the formula R⁶⁰—wherein R⁶³ is selected from the group consisting of alkyl, aryl andheteroaryl.

As used herein the term “haloalkylsulfonyl” refers to a radical of theformula

wherein the R⁶⁴ is haloalkyl as defined above.

As used herein the term “heteroaryl” refers to an aryl radical containat least one heteroatom.

As used herein the term “hydroxyalkyl” refers to a radical of theformula HO—R⁶⁵— wherein R⁶⁵ is alkylene as defined above.

As used herein the term “keto” refers to a carbonyl group joined to 2carbon atoms.

As used herein the term “lactone” refers to an anhydro cyclic esterproduced by intramolecular condensation of a hydroxy acid with theelimination of water.

As used herein the term “olefin” refers to an unsaturated hydrocarbonradical of the type C_(n)H_(2n).

As used herein the term “sulfone” refers to a radical of the formulaR⁶⁶—SO₂—.

As used herein the term “thioalkyl” refers to a radical of the formulaR⁷⁷—S— wherein R⁷⁷ is alkyl as defined above.

As used herein the term “thioether” refers to a radical of the formulaR⁷⁸—S— wherein R⁷⁷ is alkyl, aryl or heteroaryl.

As used herein the term “trifluoroalkyl” refers to an alkyl radical asdefined above substituted with three halo radicals as defined above.

The term “composition” as used herein means a product which results fromthe mixing or combining of more than one element or ingredient.

The term “pharmaceutically acceptable carrier”, as used herein means apharmaceutically acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a chemical agent.

The term “therapeutically effective amount” shall mean that amount ofdrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system or animal that is being sought by aresearcher or clinician.

The following is a list of abbreviations and the corresponding meaningsas used interchangeably herein:

-   -   ¹H-NMR=proton nuclear magnetic resonance    -   AcOH=acetic acid    -   Bn=benzyl    -   Boc=tert-butoxycarbonyl    -   Cat.=catalytic amount    -   CH₂Cl₂=dichloromethane    -   CH₃CN=acetonitrile    -   CHN analysis=carbon/hydrogen/nitrogen elemental analysis    -   DIBAL=diisobutylaluminum hydride    -   Dl water=deionized water    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   Et=ethyl    -   Etl=ethyliodide    -   Et₂O=diethyl ether    -   Et₃N=triethylamine    -   EtOAc=ethyl acetate    -   ETOH=ethanol    -   g=gram(s)    -   HPLC=high performance liquid chromatography    -   i-Pr=iso propyl    -   i-Prop=iso propyl    -   K₂CO₃=potassium carbonate    -   KOH=potassium hydroxide    -   L=Liter    -   LiOH=lithium hydroxide    -   Me=methyl    -   Mel=methyl iodide    -   MeOH=methanol    -   mg=milligram    -   MgSO₄=magnesium sulfate    -   ml=milliliter    -   mL=milliliter    -   MS=mass spectroscopy    -   MTBE=methyl t-butyl ether    -   N₂=nitrogen    -   NaH—sodium hydride    -   NaHCO₃=sodium bicarbonate    -   NaOH=sodium hydroxide    -   NaOMe=sodium methoxide    -   Na₂PO₄=sodium phosphate    -   Na₂SO₄=sodium sulfate    -   NH₄HCO₃=ammonium bicarbonate    -   NH₄ ⁺HCO2⁻=ammonium formate    -   NH₄OH=ammonium hydroxide    -   NMR=nuclear magnetic resonance    -   Pd=palladium    -   Pd/C=palladium on carbon    -   Ph=phenyl    -   Pt=platinum    -   Pt/C=platinum on carbon    -   RPHPLC=reverse phase high performance liquid chromatography    -   RT=room temperature    -   T-BOC=tert-butoxycarbonyl    -   TFA=trifluoroacetic acid    -   THF=tetrahydrofuran    -   Δ=heating the reaction mixture

The compounds as shown above can exist in various isomeric forms and allsuch isomeric forms are meant to be included. Tautomeric forms are alsoincluded as well as pharmaceutically acceptable salts of such isomersand tautomers.

In the structures and formulas herein, a bond drawn across a bond of aring can be to any available atom on the ring.

The term “pharmaceutically acceptable salt” refers to a salt prepared bycontacting a compound of Formula I with an acid whose anion is generallyconsidered suitable for human consumption. For use in medicine, thesalts of the compounds of this invention are non-toxic “pharmaceuticallyacceptable salts.” Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention which are generally prepared by reacting the free base with asuitable organic or inorganic acid. Representative salts include thefollowing: benzenesulfonate, hydrobromide and hydrochloride.Furthermore, where the compounds of the invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g., sodium or potassium salts; alkaline earthmetal salts, e.g., calcium or magnesium salts; and salts formed withsuitable organic ligands, e.g., quaternary ammonium salts. All of thepharmacologically acceptable salts may be prepared by conventionalmeans. (See Berge et al., J. Pharm. Sci., 66(1), 1-19 (1977) foradditional examples of pharmaceutically acceptable salts.) The compoundsof the present invention can have chiral centers and occur as racemates,racemic mixtures, diastereomeric mixtures, and as individualdiastereomers or enantiomers, with all isomeric forms included in thepresent invention. Therefore, where a compound is chiral, the separateenantiomers or diastereomers, substantially free of the other, areincluded within the scope of the present invention; further included areall mixtures of the enantiomers or diastereomers. Also included withinthe scope of the invention are polymorphs, or hydrates or othermodifiers of the compounds of invention.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds of this invention which arereadily convertible in vivo into the required compound. For example,prodrugs of a carboxylic acid may include an ester, an amide, or anortho-ester. Thus, in the methods of treatment of the present invention,the term “administering” shall encompass the treatment of the variousconditions described with the compound specifically disclosed or with acompound which may not be specifically disclosed, but which converts tothe compound of Formula I in vivo after administration to the patient.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in “Design of Prodrugs,”ed. H. Bundgaard, Elsevier, 1985, which is incorporated by referenceherein in its entirety. Metabolites of these compounds include activespecies produced upon introduction of compounds of this invention intothe biological milieu.

For the selective inhibition or antagonism of α_(V)β₃ and/or α_(V)β₅integrins, compounds of the present invention may be administeredorally, parenterally, or by inhalation spray, or topically in unitdosage formulations containing conventional pharmaceutically acceptablecarriers, adjuvants and vehicles. The term parenteral as used hereinincludes, for example, subcutaneous, intravenous, intramuscular,intrasternal, transmuscular infusion techniques or intraperitonally.

The compounds of the present invention are administered by any suitableroute in the form of a pharmaceutical composition adapted to such aroute, and in a dose effective for the treatment intended.Therapeutically effective doses of the compounds required to prevent orarrest the progress of or to treat the medical condition are readilyascertained by one of ordinary skill in the art using preclinical andclinical approaches familiar to the medicinal arts.

Accordingly, the present invention provides a method of treatingconditions mediated by selectively inhibiting or antagonizing theα_(V)β₃ and/or α_(V) β₅ cell surface receptor which method comprisesadministering a therapeutically effective amount of a compound selectedfrom the class of compounds depicted in the above formulas, wherein oneor more compound is administered in association with one or morenon-toxic, pharmaceutically acceptable carriers and/or diluents and/oradjuvants (collectively referred to herein as “carrier” materials) andif desired other active ingredients. More specifically, the presentinvention provides a method for selective antagonism of the α_(V)β₃and/or α_(V)β₅ cell surface receptors over α_(IIb)β₃ or α_(v)β₅ integrinreceptors. Most preferably the present invention provides a method forinhibiting bone resorption, treating osteoporosis, inhibiting humoralhypercalcemia of malignancy, treating Paget's disease, inhibiting tumormetastasis, inhibiting neoplasia (solid tumor growth), inhibitingangiogenesis including tumor angiogenesis, treating retinopathyincluding macular degeneration and diabetic retinopathy, inhibitingarthritis, psoriasis and periodontal disease, and inhibiting smoothmuscle cell migration including restenosis.

Based upon standard laboratory experimental techniques and procedureswell known and appreciated by those skilled in the art, as well ascomparisons with compounds of known usefulness, the compounds of FormulaI can be used in the treatment of patients suffering from the abovepathological conditions. One skilled in the art will recognize thatselection of the most appropriate compound of the invention is withinthe ability of one with ordinary skill in the art and will depend on avariety of factors including assessment of results obtained in standardassay and animal models.

Treatment of a patient afflicted with one of the pathological conditionscomprises administering to such a patient an amount of compound of theFormula I which is therapeutically effective in controlling thecondition or in prolonging the survivability of the patient beyond thatexpected in the absence of such treatment. As used herein, the term“inhibition” of the condition refers to slowing, interrupting, arrestingor stopping the condition and does not necessarily indicate a totalelimination of the condition. It is believed that prolonging thesurvivability of a patient, beyond being a significant advantageouseffect in and of itself, also indicates that the condition isbeneficially controlled to some extent.

As stated previously, the compounds of the invention can be used in avariety of biological, prophylactic or therapeutic areas. It iscontemplated that these compounds are useful in prevention or treatmentof any disease state or condition wherein the α_(V) β₃ and/or α_(V) β₅integrin plays a role.

The dosage regimen for the compounds and/or compositions containing thecompounds is based on a variety of factors, including the type, age,weight, sex and medical condition of the patient; the severity of thecondition; the route of administration; and the activity of theparticular compound employed. Thus the dosage regimen may vary widely.Dosage levels of the order from about 0.01 mg to about 100 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, andmost preferably 0.1 to 1.0 mg/kg/day. For oral administration, thecompositions are preferably provided in the form of tablets containing0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. A medicamenttypically contains from about 0.01 mg to about 500 mg of the activeingredient, preferably, from about 1 mg to about 100 mg of activeingredient. Intravenously, the most preferred doses will range fromabout 0.1 to about 10 mg/kg/minute during a constant rate infusion.Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, preferredcompounds for the present invention can be administered in intranasalform via topical use of suitable intranasal vehicles, or via transdermalroutes, using those forms of transdermal skin patches well known tothose of ordinary skill in the art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittant throughout the dosage regiment.

For administration to a mammal in need of such treatment, the compoundsin a therapeutically effective amount are ordinarily combined with oneor more adjuvants appropriate to the indicated route of administration.The compounds may be admixed with lactose, sucrose, starch powder,cellulose esters of alkanoic acids, cellulose alkyl esters, talc,stearic acid, magnesium stearate, magnesium oxide, sodium and calciumsalts of phosphoric and sulphuric acids, gelatin, acacia, sodiumalginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and tabletedor encapsulated for convenient administration. Alternatively, thecompounds may be dissolved in water, polyethylene glycol, propyleneglycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil,benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvantsand modes of administration are well and widely known in thepharmaceutical art.

The pharmaceutical compositions useful in the present invention may besubjected to conventional pharmaceutical operations such assterilization and/or may contain conventional pharmaceutical adjuvantssuch as preservatives, stabilizers, wetting agents, emulsifiers,buffers, etc.

The general synthetic sequences for preparing the compounds useful inthe present invention are outlined in SCHEMES 1-11. Both an explanationof, and the actual procedures for, the various aspects of the presentinvention are described where appropriate. The following SCHEMES andEXAMPLES are intended to be merely illustrative of the presentinvention, and not limiting thereof in either scope or spirit. Thosewith skill in the art will readily understand that known variations ofthe conditions and processes described in the SCHEMES and EXAMPLES canbe used to synthesize the compounds of the present invention.

SCHEME 1

The compounds of FORMULA A₁₇ are generally prepared by reacting anintermediate of formula A₁₆ with a compound of the formula A₁₅. Forexample, when Z₃ is a (OH, SH or NHR), A₁₆ may be alkylated with A₁₅(Z₄=Br or OMs) using base such as (sodium hydride, potassium hydride)preferably in a solvent such as dimethylsulfoxide or DMF. Thesereactions may preferentially be carried at 0° C. to approximately 40° C.Alternately, when Z₃ and Z₄ are both OH, the ether formation to productA₁₇ may be accomplished by using Mitsunobu reaction. This reaction maypreferentially be carried out using triarylphosphine (such astriphenylphoshine) and dialkylazodicarboxylate (such as diethylazodicarboxylate, di-tert-butyl azodicarboxylate, di-iso-propylazodicarboxylate) in solvents such as DMF, methylene chloride, THF andthe like. When Z₃ carries a carboxylic acid or a sulfonic acid and Z₄ isan amine, standard coupling conditions may be used to synthesize thetarget A₁₇ compounds containing carboxamide (CONH) or the sulfonamide(SO₂NH).

Alternately, the compounds of FORMULA A₁₇ may be prepared by startingwith compounds of general formula A₁₈. For example, when Z₅ in A₁₈ isNH₂, cyclic or acyclic guanidino containing compounds of formula A₁₇ maybe synthesized by adopting the methodologies set forth in e.g. U.S. Pat.Nos. 5,852,210, and 5,773,646, hereby incorporated by reference.Similarly, compounds of formula A₁₈ (Z₅=NH₂) may be treated withappropriately substituted heteroaromatic system (such as 2-halopyridineN-oxide) to give the target compound A₁₇. This reaction maypreferentially be carried out by refluxing the intermediate A₁₈ and2-halopyridine (such as 2-fluoropyridine, 2-chloropyridine N-oxide) insolvents such as tert-butyl alcohol, tert-amyl alcohol in the presenceof base (such as sodium bicarbonate, sodium carbonate, potassiumcarbonate, potassium bicarbonate).

When compounds of formula A₁₇ contain N-oxide (e.g., pyridine N-oxide),the deoxygenation is preferentially carried out using transferhydrogenation conditions (such as cyclohexene/Pd on carbon or ammoniumformate and Pd on carbon. When R^(b) is OR, the hydrolysis of theresulting ester may be carried out using an aqueous base such as sodiumhydroxide, lithium hydroxide, potassium hydroxide and using co-solventsas methanol, ethanol or THF.

Compounds of the general formula A₁₅, A₁₆, A₁₈ may be prepared bymethodologies discussed in SCHEMES 2-11 which follow.

SCHEME 2

Compounds of the FORMULA A₄ may be prepared by starting with asubstituted cinnamyl alcohol of formula A₁. The compounds of formula A₁may be synthesized from the corresponding cinnamic acid or its esters byreduction with e.g.; DIBAL, lithium borohydride or the like.Cyclopropanation of A₁ using Simmons-Smith reaction gives thecyclopropyl containing intermediate A₂. The conditions described in eg.; Chem. Letts; 61-64,1992; Bull. Chem. Soc., Japan, 70, 207-217,1997and the references cited therein may be used for this reaction.Oxidation of resulting alcohol (using e.g., oxalyl chloride, DMSO)followed by homologation, as described in Tetrahedron Lett 25,4549-4552,1984, gives the enol ether A₃. Hydrolysis of the enol ether A₃with e.g., 1N HCl and oxidation of the resulting aldehyde with e.g.;silver nitrate gives the acid A₄. The acid may be esterified using analcohol (such as ethanol) and an acid catalyst. The intermediate A₄ isprocessed to the compounds of Formula I by synthetic transformations asoutlined in SCHEME 1.

SCHEME 3

Compounds of FORMULA A₇ containing a cyclopentyl ring may be prepared bystarting with readily accessible intermediate A₅ by reaction of2-chloro-cyclopentanone with aryl magnesium halide (see e.g, Can. J.Chem., 70,1274-1280, 1992; Chem. Pharm. Bull., 34, 3599,1986). UsingWittig or Horner-Emmons reaction, the compound A₅ is converted to theolefin containing intermediate A₆. This reaction is carried out usingtrialkyl phosphonoacetate (such as triethyl phosphonoacetate, trimethylphosphonoacetate) and a base (e.g., sodium hydride, sodium methoxide,sodium ethoxide). This reaction is generally done at low temperature(0-30° C.) and using THF, DMF as solvents. The isomeric mixtures ofolefin containing compounds are hydrogenated using e.g., Pd on carbon orPt on carbon as catalyst. This reduction is carried under pressure ofhydrogen (preferably 5-60 psi) to give the desired intermediate A₇. Theintermediate A₇ is processed to the compounds of Formula I by synthetictransformations outlined in SCHEME 1.

SCHEME 4

Compounds of FORMULA I with a cyclopentyl ring substituted in a1,3-arrangement are prepared by starting with readily accessibleintermediate A₈. The methodology described in e.g.; J. Am. Chem. Soc.67, 286, 1945; or J. Med. Chem., 33, 2828, 1990 may be used tosynthesize A₈ with a variety of substituents on the aryl ring.Elaboration of carbonyl functionality of A₈ to intermediate A₁₀ may beaccomplished in a similar manner as described in SCHEME 3. Theintermediate A₈ is processed to the compounds of Formula I by synthetictransformations outlined in SCHEME 1.

SCHEME 5

Compounds of FORMULA I, wherein X₁ is CH₂ are prepared starting withcommercially accessible intermediate A₁₁. Reduction of the carboxylicacid functionality in A₁₁ with e g; diborane or lithium aluminum hydridegives the hydroxymethyl derivative which may be elaborated to CH₂CO₂Rfunctionality using the methodology elaborated in EXAMPLE 1.Demethylation of the intermediate with a boron trihalide such as borontribromide, boron trichloride gives the demethylated intermediates A₁₃which is processed to the compounds of Formula I by synthetictransformations as outlined in SCHEME 1.

SCHEME 6

The compounds of FORMULA I, wherein A¹ is substituted pyridyl may beprepared by adopting the general synthetic SCHEME 6. For example,reaction of substituted 2-halopyridine N-oxide (such as A_(19a)-A_(19d))with e.g. 3-aminopropanol gives the intermediates A_(20a)-A_(20d). Thisreaction may preferentially be carried out by refluxing the intermediate2-halopyridine N-oxide (such as 2-chloropyridine N-oxide) in solventssuch as tert-butyl alcohol, tert-amyl alcohol in the presence of base(such as sodium bicarbonate, sodium carbonate, potassium carbonate,potassium bicarbonate). The preparative conditions described in WO99/15508 (PCT U.S. 98/19466) may be used for this transformation.

Coupling of the intermediates A_(20a)-A_(20d) with A₁₆ using Mitsunobureaction gives the compounds containing the ether link. This reactionmay preferentially be carried out using triarylphosphine (such astriphenylphoshine) and dialkylazodicarboxylate (such as diethylazodicarboxylate, di-tert-butyl azodicarboxylate, di-iso-propylazodicarboxylate) in solvents such as DMF, methylene chloride, or THF.N-Deoxygenation of resulting intermediates followed by hydrolysis of theester gives the compounds (A_(21a)-A_(21d)).

Reduction of the N-oxide bond may be accomplished using e.g., transferhydrogenation (cyclohexene/Pd on carbon) or ammonium formate and Pd oncarbon. The nitro group in A_(21d) may be hydrogenated using Pd oncarbon or Pt on carbon as catalysts. This transformation may be carriedout using solvents such as methanol, ethanol or THF. The hydrolysis ofthe ester group may be carried using aqueous base (such as sodiumhydroxide, lithium hydroxide or potassium hydroxide) in solvents such asmethanol, ethanol and THF.

Compounds of Formula I containing a heterocycle other than pyridyl canalso be prepared using the methodology of SCHEME 6. For example reactionof 2-bromopyrimidine or 1-chloroisoquinoline N-oxide with3-amino-propanol gives the analogous intermediates as obtained in STEP 1of SCHEME 6. The resulting intermediates could be elaborated as inSCHEME 6 to give the pyrimidine and isoquinoline containing compounds ofFORMULA I.

SCHEME 7

Compounds of FORMULA I containing 6-amino substituents may be preparedas shown in SCHEME 7. The intermediate A_(22b) can be prepared asdescribed in J. Med. Chem 43, 22, 2000. Boc-protected 2-amino-6-picoline(A_(22a1)) or its ethylated derivative (A_(22c1)) are elaborated toA_(22a) and A_(22c) as shown for case A_(22b) in the above publication.The ethylated intermediate A_(22c1) may be prepared from A_(22a1) byalkylation using e.g.; Etl and a base such as potassium carbonate,cesium carbonate. This reaction may preferentially be carried out inpolar solvents such as dimethylformamide, or dimethylacetamide.Mitsunobu reaction of A₁₆, gives the compounds containing the phenolether. Removal of Boc group using e.g., trifluoroacetic acid, insolvents such as dichloromethane, followed by hydrolysis of the estergroup as discussed in SCHEME 6 above gives the compounds(A_(23a)-A_(23c)).

SCHEME 8

The cyclopropyl compounds having a substituent at the β-position to thecarboxylic acid can be prepared as shown in scheme above. For example,Horner Emmons reaction of 4-substituted benzaldehyde with triethylphosphonoalkanoate (A) gives the olefin containing intermediate. Thisreaction may be carried out in the presence of a base (e.g.; NaH, sodiumtert-butoxide and the like) in a solvent such as THF or DMF. Themethodology described in e.g.; Synthesis 661-664 (1986) and Synth.Communication 18, 1349-1362 (1988) may be used to synthesizeintermediate (A₂). The sequence of reactions described in EXAMPLE 1 canbe used to accomplish the synthesis of the target compounds (B₁ and B₂).

SCHEME 9

The target compounds of FORMULA 1 with variations in heteroarylamine A¹can be prepared following the reaction sequence shown in SCHEME 9 above.The reductive amination of arylamine (A₂₄) with an aliphatic aidehyde(A₂₅) gives the intermediate A₂₆ containing the aliphatic chain. Thisreaction may preferentially be carried out by using sodiumtriacetoxyborohydride, sodium cyanoborohydride or sodium borohydride asreducing agent and using methyene chloride, ethyl alcohol ortetrahydrofuran as solvent. Commercially accessible heteroarylamine suchas 2-amnopyridine could be used directly. In certain cases, protectedheteroaryls such as imidazole and pyrazole derived amines may be used asshown above. Desilylation of A₂₆ can be accomplished using reagents suchas cesium fluoride, potassium fluoride and the like. The generatedalcohol A₂₇ could be reacted with the substituted phenol as shown innumber of examples (for example 4). The trityl, Cbz or other protectedgroups can easily be removed by methodologies known in literature.

SCHEME 10

Compounds of FORMULA 1 containing 6-aminopyridyl system may be preparedas shown in scheme 10. The intermediate 1 can be prepared as describedin J. Med. Chem 43, 22, 2000. The hydroxyl group in 1 can be protectedas silyl ether using e.g; ter-butyldimethylsilyl chloride and imidazole.The reaction of generated intermediate with a base such as (sodiumhydride in DMF) and the alkyl halide gives the intermediate 2 afterdeprotection of the silyl ether. Mitsunobu reaction of 2 with phenolicintermediate A₃ described in scheme 8 above, gives the compoundscontaining the phenol ether. Removal of Boc group using e.g.,trifluoroacetic acid in solvents such as dichloromethane, followed byhydrolysis of the ester group as discussed in scheme 6 above gives thetarget compounds 4.

SCHEME 11

The compounds of FORMULA 1 with substituents in phenyl ring A can besynthesized as shown in the above scheme. For example, Horner Emmonsreaction of 4-substituted benzaldehyde with triethyl phosphonoacetategives the olefin containing intermediate. This reaction may be carriedout in the presence of a base (e.g.; NaH, sodium tert-butoxide and thelike) in a solvent such as THF or DMF. The intermediate can behomologated using the methodology developed by Kowalski and described inJ. Am. Chem Soc., 108,1429-30, 1985 and J. Org. Chem 57, 7194, 7208,1992. The reaction conditions described in Step 3, of EXAMPLE 1 can beused to give the cyclopropyl containing intermediate. Elaboration ofthis intermediate involving demethylation, Mitsunobu reaction,deoxygenation and hydrolysis of ester gives the target compound. Theexperimental conditions described in Steps 4-7, of SCHEME 2 can be usedto achieve the synthesis of target compound.

Alternately, the cinnamic acid derivative 2 may be elaborated to thecyclopropyl containing intermediate 3 and the target 4 following themethodology shown in example 9.

EXAMPLE A 2-[3-hydroxy-1-propylamino]pyridine-N-oxide

A mixture of 2-chloropyridine-N-oxide (16.6 g, 100 mmoles),3-amino-1-propanol (15.3 ml, 200 mmoles), NaHCO₃ (42 g, 0.5 mole), andtert-amyl alcohol (100 ml) was heated to reflux. After 23 hours, thereaction was cooled, diluted with CH₂Cl₂ (300 ml), and filtered toremove insoluble materials. The filtrate was concentrated to afford abrown oil. The oil was dried under vacuum overnight. Ether (100 ml) wasadded to give a brown solid. The ether was decanted and the solid waswashed further with ether/acetonitrile (3/1). The resulting solid washeated at 67° C. under vacuum to give the desired product (13.5 g). ¹HNMR was consistent with the proposed structure.

EXAMPLE 1 2-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid, mono(trifluoracetate)

Step 1

To a solution of trans-4-hydroxy cinnamic acid (16.4 g) and imidazole(20.4 g) in DMF (150 mL) was added a solution of t-butyldimethyl silylchloride (31.7 g) in DMF (50 mL) in one portion at room temperature. Thereaction was stirred for 1 hour and then the solvent was removed invacuo. The residual oil was partitioned between ether and 5% aqueouscitric acid. The organic portion was washed with water, and brine andthen dried over MgSO₄ and concentrated to afford a colorless oil (41.6g) which was used without further purification. The ¹H NMR wasconsistent with the proposed structure.Step 2

A solution of the product from Step 1 (30.0 g) in ether (250 mL) wasplaced in a flame dried flask under N₂ and chilled to zero degrees. Asolution of 250 mL diisobutyl aluminum hydride (200 mL) (1.0 M in THF)was added dropwise over 1 hour and stirring was continued for anadditional 1 hour at zero degrees after the addition was completed. Thereaction was then carefully quenched with saturated ammonium chloridesolution (200 mL) with vigorous stirring. The mixture was stirred for 2hours, filtered, washed with ether and the layers separated, and theorganic portion concentrated. The residual oil was purified in a silicagel column eluting with 25% ethyl acetate/hexane to afford a viscouscolorless oil (6.6 g). The ¹H NMR was consistent with the proposedstructure.Step 3

In a flame dried flask under nitrogen was placed a solution ofdiiodo-methane (2.14 g) and methylene chloride (10 mL). The solution waschilled to 0° and diethyl zinc (1.0M solution in hexane; 4.0 mL) wasadded rapidly. The solution was stirred at zero degrees for 15 minutesand then a solution of the product from Step 2 (1.0 g) in 5 mL ofmethylene chloride was added dropwise. The reaction was stirred for 90minutes while allowing to warm to room temperature and then quenchedwith water (5 mL) and partitioned between 0.25N HCl and ethyl acetate.The aqueous portion was extracted with additional solvent and thecombined organic extracts were washed with brine, dried over MgSO₄,concentrated and the residue purified on a silica gel column elutingwith 25% ethyl acetate/hexane to afford a colorless heavy liquid (510mg). The ¹H NMR was consistent with the proposed structure.Step 4

A solution of of oxalyl chloride (1.71 g) in methylene chloride (25 mL)was cooled to −60° C. under nitrogen and a solution of DMSO (2.11 g) inCH₂Cl₂ (5 mL) was added dropwise and stirring was continued for twominutes. Next, a solution of the product from Step 3 (3.3 g) in CH₂Cl₂(5 mL) was added dropwise over 5 minutes and the resultant mixture wasstirred for 15 minutes at −60° C. After this period, triethylamine (6.07g) was added rapidly and the mixture stirred at −60° C. for anadditional 5 minutes before being allowed to warm to room temperature.The reaction was diluted with water (50 mL) and extracted several timeswith methylene chloride. The combined organic extracts were thensuccessively washed with 1% HCl solution, 5% sodium carbonate solutionand brine. After drying over MgSO₄ and concentrating, the residue waspurified on a silica gel column eluting with 25% ethyl acetate/hexane toafford a light yellow liquid (2.85 g). The ¹H NMR was consistent withthe proposed structure.Step 5

To a suspension of methoxymethyl triphenylphosphonium chloride (5.14 g)in THF (15 mL) was added lithium bis (trimethylsilyl) amide (15 mL, 1.0M solution in THF) dropwise at zero degrees under nitrogen. After 15minutes a solution of the product from Step 4 (2.8 g) in THF (20 mL) wasadded dropwise and stirring continued for 15 minutes. The reaction wasthen partitioned between ether and water and the layers separated. Theaqueous portion was extracted with additional ether and the combinedorganic extracts were washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified on a silica gel column elutingwith 10% ethyl acetate/hexane to afford a liquid (1.78 g). ¹H NMR wasconsistent with the proposed structure.Step 6

A solution of the product from Step 5 (1.75 g), acetonitrile (45 mL) and1 N HCl (12 mL) was warmed to 64° C. for 15 hours under nitrogen. Thereaction was then cooled and partitioned between ether and saturatedsodium bicarbonate solution. The aqueous portion was extractedthoroughly with additional ether and the combined organic extracts werewashed with brine, dried over Na₂SO₄, and concentrated. The residue waspurified on a silica gel column eluting with 35% ethyl acetate/hexane toafford a viscous oil (491 mg). ¹H NMR spectra was consistent with theproposed structure.Step 7

To a suspension of the product from Step 6 (490 mg) in water (5 mL) wassuccessively added a solution of silver nitrate (1.0 g) in water (5 mL)and sodium hydroxide(480 mg) in water (5 mL) at room temperature. Theblack mixture was stirred for 1 hour and then filtered through a pad ofcelite. The filtrate was acidified with 1N HCl and extracted with ethylacetate. The combined organic extracts were dried over Na₂SO₄ andconcentrated to a brown residue which was treated with a 1:1 mixture ofethanol and 4N HCl/dioxane (30 mL) at room temperature for 18 hours. Thereaction was concentrated and the residue was purified on a silica gelcolumn eluting with 25% ethyl acetate/hexane to afford a golden oil (226mg). ¹H NMR spectra was consistent with the proposed structure.Step 8

To a solution of the product from Step 7 (220 mg) in DMF (3 mL) undernitrogen was added 2-[3-hydroxy-1-propyl)amino] pyridine-N-oxide(Example A) and triphenylphosphine (315 mg). The solution was stirred atroom temperature for several minutes and then a solution of diethylazodicarboxylate (209 mg) in DMF (2 mL) was added dropwise. The reactionwas stirred for 18 hours and the solvent was removed in vacuo. Theresidue was purified on a silica gel column eluting with 94% CH₂Cl₂₋₅%CH₃OH-1% NH₄OH to afford a viscous golden oil (125 mg). ¹H NMR wasconsistent with the proposed structure.Step 9

A mixture of the product from Step 8 (120 mg), 10% Pd on carbon (125mg), cyclohexene (1.0 mL) and isopropanol (10 mL) was refluxed for 3hours. The reaction mixture was cooled, filtered through a pad of celiteand washed with excess isopropanol. The filtrate was concentrated andthe residue was purified on a silica gel column eluting with 97%CH₂Cl_(2-2.5)% CH₃OH and 0.5% NH₄OH to afford a colorless oil (74 mg).¹H NMR was consistent with the proposed structure.Step 10

A solution of the product from Step 9 (70 mg) in methanol (5 mL) and 1 Nsodium hydroxide (5 mL) was stirred at room temperature for 18 hours.The reaction mixture was quenched with trifluoroacetic acid (1 mL) andconcentrated. The residue was purified on a reverse place HPLC usingacetonitrile/water (0.5%.TFA) gradient to give the desired product as aviscous oil (36 mg). Elemental analysis: calcd. for C₁₉H₂₂N₂O₃.TFA C,57.27; H, 5.26; N, 6.36; Found: C, 57.99; H, 5.44; N, 6.27; ¹H NMR wasconsistent with the proposed structure.

EXAMPLE 2 2-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopentaneaceticAcid

Step 1

In a flame dried flask under N₂ was placed a solution of2-chlorocyclopentanone (10.0 g) in diethyl ether (50 mL). While stirringat room temperature, 4-methoxyphenylmagnesium bromide (170 mL; 0.5 Msolution in THF) was added dropwise. An exothermal reaction ensued andstirring was continued for an additional 30 minutes after the additionwas completed. The reaction was quenched with 1N HCl (150 mL) and thelayers were separated. The aqueous portion was extracted with ethylacetate and then the combined organic portions were washed with waterand brine and then dried (Na₂SO₄) and concentrated. The residue waspurified on a silica gel column eluting with 25% ethyl acetate/hexane toafford a dark oil (4.1 g). ¹H NMR was consistent with the proposedstructure.

Step 2

In a flame dried flask under N₂ was suspended sodium hydride (310 mg,60% dispersion) in THF (10 mL). A solution of triethylphosphonoacetate(1.74 g) in THF (5 mL) was added dropwise and the reaction was allowedto stir at room temperature for 30 minutes. A solution of the productfrom Step 1 (1.0 g) in THF (5 mL) was added in one portion and thereaction brought to reflux for 1 hour. The reaction was cooled andpartitioned between 1 N HCl and ethyl acetate. The aqueous portion wasextracted with additional ethyl acetate and the combined organicextracts were washed with water, brine, dried (Na₂SO₄), andconcentrated. The residue was purified on a silica gel column elutingwith 20% ethyl acetate/hexane to afford a liquid (800 mg). ¹H NMR wasconsistent with the proposed structure.

Step 3

A solution of the product from Step 2 (800 mg) in ethanol was shaken ina Parr hydrogenation apparatus with 5% Pd/C under 60 psi hydrogenpressure at room temperature for 3 hours. The reaction mixture was thenfiltered and concentrated and the residual oil (691 mg) was used withoutfurther purification in the next step. ¹H NMR was consistent with theproposed structure.

Step 4

To a solution of the product from Step 3 (2.70 g) in methylene chloride(15 mL) was added boron tribromide (25 mL, 1.0 M solution in CH₂Cl₂)over 10 minutes at room temperature. After stirring at room temperaturefor 1 hour, the reaction was quenched with ethanol and thenconcentrated. The residue was partitioned between ethyl acetate and 10%sodium bicarbonate solution. The aqueous portion was extracted withadditional solvent and the combined organic solvents were washed withbrine, dried over Na₂SO₄, concentrated, and the residue purified on asilica gel column eluting with 25% ethyl acetate/hexane to afford agolden oil (1.74 g). ¹H NMR was consistent with the proposed structure.

Step 5

The title compound produced in Step 5 was prepared from the productdescribed in Step 4 (1.60 g) using the same procedure as described inStep 8 of Example 1. The crude product was purified on a silica gelcolumn eluting with 95% CH₂Cl₂₋₄% CH₃OH-1%NH₄OH to afford a golden oil(2.08 g). ¹H NMR was consistent with the proposed structure.

Step 6

The compound produced in Step 6 was prepared from the product describedin Step 5 (2.0 g) using the same procedure as described in Step 9 ofExample 1. The crude product was purified on a silica gel column elutingwith 97% CH₂Cl₂₋₂% CH₃OH-1% NH₄OH to afford a viscous oil (1.2 g). ¹HNMR was consistent with the proposed structure.

Step 7

The title compound was prepared from the product described in Step 6(500 mg) using the same procedure as described in Step 10 of Example 1.The crude product was purified in similar fashion to afford a viscouscolorless glass (272 mg). Elemental analysis: Calculated forC₂₁H₂₆N₂O_(3.)1.5 TFA. 0.25H₂O: C, 54.39; H, 5.33; N, 5.29; Found: C,54.35; H, 5.46; N, 5.31. ¹H-NMR was consistent with the proposedstructure.

EXAMPLE 3 3-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopentaneaceticAcid

Step 1

The starting material was prepared according to the procedure of Wildsand Johnson, J.A.C.S., 67,286-290, 1945. The compound was prepared from3-(4-methoxyphenyl) cyclopentenone (2.5 g) using the same procedure asdescribed in Step 2 of Example 2. The crude product was purified on asilica gel column eluting with 30% ethyl acetate/hexane to afford anorange solid (1.53 g). ¹H NMR was consistent with the proposedstructure.

Step 2

A solution of the product from Step 1 (1.5 g) in ethanol was shaken in aParr hydrogenation apparatus with 4% Pd/C under 5 psi hydrogen pressureat room temperature for 8 hours. The reaction mixture was filtered andconcentrated and the crude product was purified on a silica gel columneluting with 25% ethyl acetate/hexane to afford a liquid (1.35 g). ¹HNMR was consistent with the proposed structure.

Step 3

The compound produced in Step 3 was prepared from the product describedin Step 2 (1.3 g) using the same procedure described in Step 4 ofExample 2. The crude product was purified on a silica gel column elutingwith 30% ethyl acetate/Hexane to afford a liquid (1.22 g). ¹H NMR wasconsistent with the proposed structure.

Step 4

The compound produced in Step 4 was prepared from the product describedin Step 3 (600 mg) using the same procedure described in Step 8 ofExample 1. The crude product was purified on a silica gel column elutingwith 96.5% CH₂Cl_(2-3.0)% CH₃OH-0.5% NH₄OH to afford a golden oil (606mg). ¹H NMR was consistent with the proposed structure.

Step 5

The compound produced in Step 5 was prepared from the product describedin Step 4 (595 mg) using the same procedure described in Step 9 ofExample 1. The crude product was purified on a silica gel column elutingwith 97.5% CH₂Cl_(2-2.0)% CH₃OH-0.5% NH₄OH to afford a semi solid (320mg). ¹H NMR was consistent with the proposed structure.

Step 6

The title compound was prepared from the product described in Step 5(310 mg) using the same procedure described in Step 10 of Example 1. Thecrude product was purified in similar fashion to afford a white solid(191 mg). Analysis: Calculated for C₂₁H₂₆N₂O_(3.)1.0 TFA: C, 58.97; H,5.81; N, 5.98; Found: C, 58.70; H, 5.81: N, 5.92. ¹H NMR was consistentwith the proposed structure.

EXAMPLE 42,2-difluoro-3-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

Step 1

A solution of 4-methoxy trans cinnamic acid (20 g) in absolute ethanol(300 ml) and 4N HCl/dioxane (100 ml) was stirred at room temperature for16 hours. The solution was concentrated and the residue was purified ona silica gel column eluting with 25% ethyl acetate/hexane to afford alow melting solid (17.5 g) which solidified to a glass upon standing atroom temperature. The ¹H NMR was consistent with the proposed structure.

Step 2

In a flame dried flask under nitrogen was placed a solution of2,2,6,6-tetramethylpiperidine (24.66 g) in THF (150 ml) and chilled to00. A solution of n-BuLi (2.5 M in hexane; 64 ml) was added dropwiseover 10 minutes and stirring was continued for an additional 15 minutesafter the addition was completed. This solution was then added dropwiseto a solution of dibromomethane (27.8 g) in THF (150 ml) in anotherflame dried flask under nitrogen at −700. After 5 minutes a solution ofthe ester (10.0 g) from Step 1 in THF (50 ml) was added dropwise over 5minutes and 10 minutes later additional 2,2,6,6-tetramethylpiperidine(6.85 g) was added followed by n-BuLi (2.5 M in hexane; 155 ml)dropwise. The cooling bath was then replaced by a water bath at roomtemperature and after the reaction was stirred for 15 minutes it waspoured into an ice cold acidic ethanol solution (prepared from 125 ml ofacetyl chloride in 625 ml of ethanol). The mixture was then extractedseveral times with ether and the combined extracts were washed with 10%sulfuric acid, 5% sodium bicarbonate solution, brine and dried (Na₂SO₄).The filtered solution was concentrated and the residue was purified on asilica gel column eluting with 20% ethyl acetate/hexane to afford a darkred oil (2.46 g). The ¹H NMR was consistent with the proposed structure.

Step 3

A mixture of the ester (2.4 g) from Step 2, sodium chlorodifluoroacetate(10.7 g) and diglyme (90 ml) was refluxed under N₂ for 16 hours. Thereaction was cooled and partitioned between ethyl acetate and water. Theaqueous portion was extracted with additional ethyl acetate and thecombined organic extracts were washed with water, brine, and dried(Na₂SO₄). The filtered solution was concentrated and the residue waspurified on a silica gel column eluting with 20% ethyl acetate/hexane toafford a golden oil (1.23 g). The ¹H NMR was consistent with theproposed structure.

Step 4

A solution of the ester (1.2 g) from Step 3 in methylene chloride (25ml) was chilled to 0° under N₂ and treated dropwise with borontribromide (1.0 M in methylene chloride; 10 ml). The reaction wasstirred for 30 minutes while allowing to warm to room temperature. Thereaction was then carefully quenched with ethanol (10 ml), stirred for15 minutes and concentrated. The reaction was partitioned between ethylacetate and 10% sodium bicarbonate solution. The aqueous portion wasextracted with additional ethyl acetate and the combined organicextracts were washed with brine and dried (Na₂SO₄). The filteredsolution was concentrated and the residue was purified on a silica gelcolumn eluting with 30% ethyl acetate/hexane to afford a light yellowsolid (863 mg). The ¹H NMR was consistent with the proposed structure.

Step 5

To a solution of the product from Step 4 (1.0 g) in THF (25 ml) undernitrogen was added 2-[(3-hydroxy-1-propyl)amino] pyridine-N-oxide (841mg) and triphenylphosphine (1.31 g). The solution was stirred at roomtemperature for several minutes and then a solution ofdiethylazodicarboxylate (871 mg) in THF (15 ml) was added dropwise. Thereaction was stirred for 18 hours and the solvent was removed in vacuo.The residue was purified on a silica gel column eluting with 97%CH₂Cl_(2-2.5)% CH₃OH-0.5% NH₄OH to afford a golden oil (1.02 g). The ¹HNMR was consistent with the proposed structure.

Step 6

A mixture of the product of Step 5 (500 mg), 10% Pd on carbon (128 mg),ammonium formate (543 mg) and methanol (10 ml) was stirred at roomtemperature for 20 hours. The reaction mixture was concentrated and theresidue was purified on a silica gel column eluting with 97.5% CH₂Cl₂₋₂%CH₃OH-0.5% NH₄OH to afford a viscous oil (189 mg). The ¹H NMR wasconsistent with the proposed structure.

Step 7

A solution of the product from Step 6 (180 mg) in methanol (5 ml) and 1Nsodium hydroxide (5 ml) was stirred at room temperature for 6 hours. Thereaction was quenched with trifluoroacetic acid (2 ml) and concentrated.The residue was purified on a reverse phase HPLC usingacetonitrile/water (0.5% TFA) gradient to give the desired product as aviscous oil (80 mg). The ¹H NMR was consistent with the proposedstructure. Elemental analysis: calculated for C₁₉H₂₀N₂F₂O₃.TFA: C,52.95; H, 4.44; N, 5.88; Found: C, 52.39; H, 4.60; N, 5.62.

EXAMPLE 5(2-{4-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

Step 12-(3-methyl-2-pyridinyl)1H-isoindole-1,3 (2H)-dione

To a neat 2-amino-3-picoline (91 g, 0.84 mol) was addedphthalicanhydrous (125 g, 0.84 mol), the resulting solid mixture washeated at 120° C. and water was distilled off from the reaction mixture.The reaction mixture was cooled to room temperature and solid wasdissolved in methylenechloride (1 L). The organic solution was washedwith water (2×500 ml), brine (1×500 ml), dried over MgSO₄. The colorsolution was treated with activated carbon, filtered and filtrate wasconcentrated under reduced pressure. Ether (300 ml) was added to theconcentrated residue and stirred at room temperature overnight. Solidwas filtered and washed with ether, dried to give 176 g (88%) whitesolid. NMR (DMSO) δ 2.17 (m, 3H), 7.46-7.49 (m, 1H), 7.88-8.01 (m, 5H),8.44-8.46 (m, 1H). Mass spectrometry: 239.19 (M+H)⁺.

Step 2

2-[3-(dibromomethyl)-2-pyridinyl]-1H-isoindole-1,3(2H)-dione

To a suspension solution of 2-(3-methyl-2-pyridinyl)1H-isoindole-1,3(2H)-dione (14.6 g, 61 mmol) and NBS (25 g, 140 mmol) in CCl₄ (160 mL)was added AIBN (0.1 g), the reaction mixture was refluxed and airradiated with a sun lamp. AIBN (0.1 g) were added every 30 minutesuntil the starting material was all consumed. The mixture was cooled toroom temperature and solid was filtered. Solid was taken up tomethylenechlorid (400 ml) and washed with 5% Na₂S₂O₃ (3×150 ml), water(1×150 ml) and dried over Na₂SO₄. The solvent was removed under reducedpressure. The concentrated solid was suspended in ether. Solid wasfiltered and dried to give 20.5 g (84.5%) yellow solid. NMR (DMSO) δ 7.6(s, 1H), 7.74-7.78(m, 1H), 7.92-8.01 (m, 4H), 8.51-8.55 (m, 1H),8.63-8.64 (m, 1H). Mass spectrometry: 396.92 (M+H)⁺.

Step 3

2-amino-3-pyridinecarboxaldehyde

The compound was prepared according to the procedure as described by A.E. Moormann et al, Synthetic Communications, 17(14), 1695-1699 (1987) Toa solution of2-[3-(dibromomethyl)-2-pyridinyl]-1H-isoindole-1,3(2H)-dione (20 g, 50mmol) in ethanol (250 ml) was added conc. NH₄OH (25 ml) at 4° C. Thereaction mixture was stirred 10 minutes at 4° C. then stirred at roomtemperature for one hour. Reaction mixture was concentrated underreduced pressure. To the concentrated residue was added con. HCl (150ml) and mixture was refluxed for 3 hours. The reaction mixture wascooled to room temperature and concentrated. To the concentrated residuewas added water (25 ml) then added saturated K₂CO₃ to neutralize thesolution. The solution was extracted with methylenechloride (3×150 ml).Combined organic solution was washed with water (3×150 ml), brine (1×200ml), dried over Na₂SO₄, concentrated. The concentrated residue wassuspended in ether, filtered and washed with ether to give 4.3 g (70%)yellow solid. NMR (DMSO) δ 6.69-6.73 (m, 1H), 7.51 (bs, 2H),7.95-7.98(m, 1H), 8.20-8.22 (m, 1H), 9.82 (s, 1H).

Step 4

2-methyl-1,8-naphthyridine

The compound was prepared according to the procedure as described by E.M. Hawes and D. G. Wibberley, J. Chem. Soc. (C), 1966, 315. To asolution of 2-amino-3-pyridinecarboxaldehyde (2 g, 16 mmol) in ethanol 3ml) was added acetone (1.9 g, 32 mmol) and peperidine (0,34 g, 4 mmol)and the reaction mixture was refluxed 24 hours. Reaction mixture wascooled to room temperature then concentrated in vacuum. Ether was addedto concentrated residue. Solid was filtered and dried to give 1.62 g(69%) yellow solid. NMR (CD₃OD) δ 2.76 (s, 3H), 7.52-7.58 (m, 2H), 8.30(d, 2H, J=8.33 Hz), 8.36-8.39 (m, 1H), 8.39-8.99 (m, 1H).

Step 5

2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridine

The compound was prepared according to the procedure as described in WO0033838. To a solution of 2-methyl-1,8-naphthyridine (2 g, 13.9 mmol) inethanol (35 ml) was added 10% Pd/C, and the reaction mixture was stirredunder H₂ (10 psi) for 24 hours. Palladium was filtered out throughcelite and washed with excess ethanol. The filtrate was concentratedunder vacuum to give 1.7 g (83%) pink solid. NMR (CD₃OD) δ 1.82-1.87 (m,2H), 2.22 (s, 3H), 2.65-2.76 (m, 2H), 3.33-3.36 (m, 2H), 6.32 (d, 1H,J=7.25 Hz), 7.07 (d, 1H, J=7.38 Hz). Mass spectrometry: 149.15 (M+H)⁺.

Step 6

2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine

The compound was prepared according to the procedure as described in WO0033838. To a solution of 2-methyl-5,6,7,8-tetrahydro-1,8-naphthyridine(1 g, 6.7 mmol) in methylenechloride (10 ml) was added di-tert-butyldicarbonate (3 g, 13 mmol), triethylamine (0.68 g, 6.7 mmol) and 4-DMAP(50 mg), the reaction mixture was refluxed overnight. The reactionmixture was concentrated under vacuum. The concentrated residue waspurified on silica gel (1% methanol in methylenechloride) to give 1.1 g(69%) orange solid. NMR (CD₃OD) δ 1.50 (s, 9H),1.88-1.95 (m, 2H), 2.43(s, 3H), 2.73-2.78 (m, 2H), 3.29-3.31 (m, 2H), 3.72-3.76 (m, 2H), 6.95(d, 1H, J=7.76 Hz), 7.44 (d, 1H, J=7.76 Hz).

Step 7

Ethyl[8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]acetate

The compound was prepared according to the procedure as described in WO0033838. To a solution of2-methyl-8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridine(1.4 g, 5.6 mmol) and diethylcarbonate (2.5 g, 20 mmol) in THF (10 ml)was added LDA (8 ml of 2M solution in hexane) at −78° C. and stirred at−78° C. for 40 minutes. The reaction was quenched with saturated NH₄Cland extracted with ethylacetate (2×100 ml). Combined organic solutionwas concentrated and purified on silica gel column to give 1.5 g (83%)yellow oil. NMR (CD₃OD) δ 1.25 (t, 3H, J=7.10 Hz), 1.51 (s, 9H),1.88-1.97 (m, 2H), 2.75 (t, 2H, J=6.59 Hz), 3.74-3.80 (m, 4H), 4.10-4.20(m, 2H), 7.0 (d, 1H, J=7.61 Hz), 7.39 (d, 1H, J=7.47 Hz).

Step 8

2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol

The compound was prepared according to the procedure as described in WO0033838. To a solution of ethyl[8-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]acetate(3.8 g, 11.8 mmol) in THF (20 ml) was added LiBH₄ (7.6 ml of 2M solutionin hexane, 15.2 mmol), the reaction was refluxed overnight. The reactionmixture was cooled in ice bath and quenched with water. The mixture wasextracted with ethylacetate (3×50 ml). The combined organic solution wasdried over MgSO₄, concentrated and dried under vacuum to give 2.9 g oil.The oil was taken up in methylenechloride (10 ml) and 4N HCl in dioxane(10 ml) was added. The solution was stirred 4 hours at room temperaturethen concentrated under vacuum. To the concentrated residue was added1:1/1N NaOH:brine (50 ml) and extracted with methylenechloride (3×80ml). The combine organic solution was concentrated and purified onsilica gel to give 1 g (47%) oil. NMR (CD₃OD) δ 1.82-1.88 (m, 2H),2.66-2.71 (m, 4H), 3.45 (t, 2H, J=5.57 Hz), 3.77 (t, 2H, J=6.84 Hz),6.36 (d, 1H, J=7.38 Hz), 7.10 (d, 1H, J=7.38 Hz).

Step 9

To a solution of 2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)-1-ethanol(WO 00/33838; 0.18 g, 1 mmole) and PPh3 (0.26 g, 1 mmole) in dry THF (4mL) was added cyclopropyl phenol (0.1 g, 0.45 mmole) in dry THF (3 mL)and diisopropyl azodicarboxylate (0.17 g, 1 mmole). The reaction mixturewas stirred at room temperature. After 18 hours, the mixture wasconcentrated under reduced pressure and purified on reverse phase HPLC.The ethyl ester of title compound (0.1 g, 45%) was dissolved in 3 mL 50%acetonitrile in water and LiOH (40 mg) was added. The reaction mixturewas heated at 50° C. for one hour then acidified by adding TFA. Theresidue was purified on reverse phase HPLC to give the title compound(50 mg, 53%) as TFA salt: HRMS: (MH+)=353.1876. NMR (400 MHz, CD₃OD) δ0.76-0.84(??m, 1H), 0.85-0.88 (m, 1H), 1.20-1.24 (m, 1H), 1.68-1.71 (m,1H), 1.90-1.96 (m, 2H), 2.28-2.40 (m, 2H), 2.80 (t, 2H, J=6.24 Hz), 3.10(t, 2H, J=5.98 Hz), 3.48 (t, 2H, J=5.71 Hz), 4.22 (t, 2H, J=5.97 Hz),6.70 (d, 1H, J=7.38 Hz), 6.76-6.79 (m, 2H), 6.98-7.01 (m, 2H), 7.57 (d,1H, J=7.38 Hz).

EXAMPLE 62-[3-methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

Step 1

4-hydroxy-3-methylbenzaldehyde (3.0 g, 22 mmol) was dissolved in DMF (25ml). Imidazole (2.72 g, 40 ml) and dimethyl-t-butylsilyl chloride (3.76g, 25 mmol) were added. After 30 min, the product was extracted withethyl acetate, and washed with H₂O. The aqueous layer was extracted withadditional ethyl acetate. The combined organic layer was washed withH₂O, brine, and dried. The crude product was purified by vacuumdistillation to afford a clean oil in 4.1 g. NMR spectra of the productwere consistent for the proposed structure.

Step 2

Under N₂, a solution of triethyl phosphonoacetate (4.5 g, 20 mmol) in 40ml THF was added to a suspension of sodium hydride (0.8 g, 20 mmol, 60%dispersion in mineral oil) in 40 ml THF at 0° C. The resulting mixturewas stirred at 0° C. for 30 min. A solution of the product of step 1(4.1 g, 16.4 mmol) in 20 ml THF was added. The reaction was allowed towarm to room temperature and then was stirred at reflux for 1 h. Thecooled reaction was quenched with 1N HCl solution. The product wasextracted with ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate. The combined ethyl acetate layer was washedwith H₂O and brine, dried with Na₂SO₄, and concentrated. The residue waspurified by chromatography (on silica gel, EA/hexane5/95) to give acolorless liquid in 4.5 g. NMR spectra of the product were consistentfor the proposed structure.

Step 3

A solution of n-BuLi (12.4 ml, 30.9 mmol, 2.5M in hexane) was added to asolution of 2,2,6,6-tetramethylpiperidine (4.8 g, 33.7 mmol) in 35 mlTHF at 0° C. to form LTMP. In a separate flask, a solution of theproduct of step 2 (4.5 g, 14.04 mmol) and dibromomethane (5.3 g, 30.9mmol) in 30 ml of THF was cooled to −70° C. After 30 min, LTMP solutionwas cooled to −70° C., and added to above solution via a cannula over 30min at −65° C. After 10 min, a solution of lithium bis(trimethyl)silylamide solution (28 ml, 28 mmol, 1M in THF) was added over 15 min at −70°C. The resulting mixture was allowed to warm to −20° C. and then cooledback to −70° C. A solution of s-BuLi solution (43.2 ml, 56.2 mmol, 1.3 Min cyclohexane) was added at −60° C. over 15 min. The mixture wasallowed to warm to room temperature. A solution of n-BuLi (12.4 ml, 28mmol, 2.5 in hexane) was added to the reaction, and the reaction wasstirred at room temperature for 1 h. The reaction was cooled to −70° C.and transferred into an acidic ethanol solution (15 ml acetyl chlorideand 75 ml ethanol) at 0° C. via a cannula over 1 h. The resultingmixture was diluted with 280 ml ether and washed with 280 ml 10% HClsolution. The aqueous layer was extracted with ether. The combinedorganic layer was washed with brine, dried with MgSO₄, and concentrated.The residue was purified by chromatography (on silica gel, ethylacetate/hexane=5/95) to give a brown liquid in 1.65 g. NMR spectra ofthe product were consistent for the proposed structure.

Step 4

Under N₂, a solution of diethyl zinc (5.5 ml, 5.5 mmol, 1.0 M in hexane)was added to a solution of diiodomethane (2.95 g, 11.0 mmol) in 15 mldichloromethane at 0° C. After 15 min, a solution of the product of step3 (1.65 g, 4.9 mmol) in 5 ml dichloromethane was added at 0° C.dropwise. The reaction was warmed to 35° C. After 30 min, the reactionwas cooled to 0° C. and quenched with H₂O. The product was extractedwith ethyl acetate and washed with 1N HCl. The aqueous layer wasextracted with ethyl acetate. The combine organic layer was washed withH₂O, brine, dried with Na_(0.2)SO₄, and concentrated to give a brown oilin 1.22 g. This product was used without further purification. NMRspectra of the product were consistent for the proposed structure.

Step 5

Potassium fluoride (0.3 g, 5.1 mmol) was added to a solution of theproduct of step 4 (1.22 g, 3.5 mmol) in 15 ml DMF and 1.0 ml H₂O. Thereaction was stirred at room temperature for 18 h. The product wasextracted with ethyl acetate. The aqueous layer was extracted with anadditional ethyl acetate. The combined organic layer was washed withH₂O, brine, dried with Na₂SO₄, and concentrated. The residue waspurified by chromatography (on silica gel, EA/hexane=3/7) to yield apale brown oil in 0.373 g. This product was used without furtherpurification. NMR spectra of the product were consistent for theproposed structure.

Step 6

A solution of diethyl azodicarboxylate (0.348 g, 2.0 mmol) in 3 ml THFwas added to a solution of the product of step 5 (0.37 g, 1.6 mmol) andtriphenylphosphine (0.525 g, 2.0 mmol) in 12 ml THF at room temperature.After 15 min, 2-(3-Hydroxypropylamino)pyridine N-oxide (0.336 g, 2 mmol)was added. The reaction was stirred at room temperature for 18 h andconcentrated. The residue was purified by chromatography (on silica gel,C₂HCl₂/CH₃OH/NH₄OH=98.5/1/0.5) to yield a pale brown oil in 0.127 g. NMRspectra of the product were consistent for the proposed structure.

Step 7

A solution of the product of step 6 (0.25 g, 0.65 mmol), ammoniumformate (0.41 g, 6.5 mmol), and 10% palladium on carbon (0.075 g, 0.07mmol) in 5 ml methanol was stirred at room temperature for 20 h.Additional ammonium formate (0.41 g, 6.5 mmol) and 10% Palladium oncarbon (0.075 g, 0.07 mmol) were added. After 20 h, the reaction wasfiltered through a short column of Celite® and washed with ethanol. Thefiltrate was concentrated and residue was purified by chromatography (onsilica gel, C₂HCl₂/CH₃OH/NH₄OH=98.5/1/0.5) to afford a pale brown oil in0.127 g). NMR spectra of the product were consistent for the proposedstructure.

Step 8

A solution of the product of step 7 (0.095 g, 0.26 mmol) in 5 ml 1 NNaOH and 5 ml methanol was stirred at room temperature for 18 h. Thereaction was acidified with 1.5 ml trifluoroacetic acid andconcentrated. The residue was purified on HPLC using acetonitrilegradient 10-50% in 30 min to yield 40.3 mg. FAB-MS:(MH+)=341.4. ¹H NMR(CDCl₃) δ 0.81 (dt, 1H), 0.99 (dt, 1H), 1.31 (m, 1H), 1.71 (dt, 1lH),2.19 (s, 3H), 2.19 (p, 2H), 2.43 (d, 2H), 3.54 (q, 2H), 4.03 (t, 2H),6.71 (m, 2H), 6.83 (d, 1H), 6.89 (m, 2H), 7.76 (t, 1H), 7.80 (d, 1H),9.61 (br, 1H). Anal Calcd. for C₂₀H₂₄N₂O₃ plus 1.25 CF₃COOH: C, 55.96;H, 5.27; N, 5.80. Found: C, 56.05; H, 5.47; N, 5.78.

EXAMPLE 72-[2-methoxy-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

The title compound was prepared according to the general proceduresdescribed for the preparation of EXAMPLE 6:H NMR(CDCl3) δ 0.78 (dt, 1H),0.96 (dt, 1H), 1.19 (m, 1H), 1.86 (dt, 1lH), 2.19 (p, 2H), 2.38 (dd,1H), 2.56 (dd, 1H), 3.51 (t, 2H), 3.83 (s, 3H), 4.06 (t, 2H), 6.39 (dd,1H), 6.44 (d, 1H), 6.69 (t, 1H), 6.81 (d, 1H), 6.85 (d, 1H), 7.75 (t,1H), 7.77 (d, 1H). Anal Calcd. for C₂₀H₂₄N₂O₄ plus 0.9 CF₃COOH: C,57.04; H, 5.47; N, 6.10. Found: C, 57.08; H, 5.38; N, 6.21.

EXAMPLE 82-[2-methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

Step 1

3,4-Dimethyl anisole (6.0 g, 44.0 mmol) was dissolved in 200 mlmethanol. A solution of ammonium cerium (IV) nitrate in 300 ml methanolwas added at room temperature over 5 min and the reaction was stirredfor 10 min. The reaction was diluted with 300 ml H₂O. The product wasextracted with dichloromethane. The organic layer was washed with brine,dried with Na₂SO₄, and concentrated. The residue was purified bychromatography (on silica gel, ethyl acetate/hexane=1/9) to afford agreenish liquid in 5.7 g. NMR spectra of the product were consistent forthe proposed structure.

Step 2

A solution of triethyl phosphonoacetate (11.2 g, 50 mmol) in 50 ml THFwas added to a mixture of sodium hydride (1.2 g, 50 mmol) in 50 ml THFat 0° C. After 30 min, a solution of the product of step 1 (5.7 g, 40mmol) in 25 ml THF was added at 0° C. The reaction was heated at refluxfor 1 h. The reaction was diluted with ethyl acetate, and 1N HClsolution. The aqueous layer was extracted with additional ethyl acetate.The combined organic layer was washed with H₂O, brine, dried withNa₂SO₄, and concentrated. The residue was purified by chromatography (onsilica gel, ethyl acetate/hexane=15/85) to give a colorless liquid in7.89 g. NMR spectra of the product were consistent for the proposedstructure.

Step 3

A solution of n-butyllithium (17.6 ml, 44 mmol, 2.5M in hexane) wasadded to a solution of 2,2,6,6-tetramethylpiperidine (6.8 g, 48 mmol) in50 ml THF at 0° C. to form LTMP. In a separate flask, a solution of theproduct of step 2 (4.4 g, 20 mmol) and dibromomethane (7.6 g, 44 mmol)in 40 ml THF was cooled to −70° C. After 30 min, LTMP solution wascooled to −70° C., and added to above solution via a cannula at −65° C.over 30 min. After 10 min, a solution of lithium bis(trimethyl)silylamide solution (40 ml, 40 mmol, 1M in THF) was added over 15 min at −70°C. The resulting mixture was allowed to warm to −20° C. and then cooledback to −70° C. A solution of s-butyllithium solution (61.6 ml, 80 mmol,1.3 M in cyclohexane) was added at −60° C. over 15 min. The mixture waswarmed to room temperature. A solution of n-BuLi (17.6 ml, 40 mmol, 2.5in hexane) was added, and the reaction was stirred at room temperaturefor 1 h. It was cooled to −70° C. and transferred into an acidic ethanolsolution (20 ml acetyl chloride and 100 ml ethanol) at 0° C. via acannula over 1 h period. The resulting mixture was diluted with 400 mlether and washed with 400 ml 10% HCl solution. The aqueous layer wasextracted with ether. The combined organic layer was washed with brine,dried with MgSO₄, and concentrated. The residue was purified bychromatography (on silica gel, ethyl acetate/hexane=1/9) to give a brownliquid in 1.17 g. NMR spectra of the product were consistent for theproposed structure.

Step 4

Under N₂, diethyl zinc solution (5.5 ml, 5.5 mmol, 1.0 M in hexane) wasadded to a solution of diiodomethane (2.95 g, 11 mmol) in 15 mldichloromethane at 0° C. After 15 min, a solution of the product of step3 (1.15 g, 4.9 mmol) in 5 ml dichloromethane was added dropwise at 0° C.The reaction was heated at 35° C. for 30 min. The reaction was quenchedwith H₂O at 0° C. and acidified with 1N HCl. The product was extractedwith ethyl acetate. The aqueous layer was extracted with additionalethyl acetate. The combined organic layer was washed with H₂O, brine,dried with Na₂SO₄, and concentrated to afford a brown oil in 1.42 g.This product was used without further purification. NMR spectra of theproduct were consistent for the proposed structure.

Step 5

The product of step 4 (1.42 g, 5.7 mmol) was dissolved in 15 mldichloromethane. Under N₂ boron tribromide solution (11 ml, 11 mmol, 1Min dichloromethane) was added to the above solution dropwise at 0° C.The reaction was allowed to warm to room temperature. After 30 min, thereaction was carefully quenched with ethanol. The product was extractedwith ethyl acetate and washed with 1N HCl. The organic layer was furtherwashed with 5% NaHCO₃ solution, brine, dried with MgSO₄, andconcentrated. The residue was purified by chromatography (on silica gel,ethyl acetate/hexane=2/8) to give a pale brown oil in 0.175 g. NMRspectra of the product were consistent for the proposed structure.

Step 6 A solution of diethyl azodicarboxylate (174 mg, 1.0 mmol) in 1 mlTHF was added to a solution of the product of step 5 (175 mg, 0.75 mmol)and triphenylphosphine (262 mg, 1 mmol) in 5 ml THF at room temperatureand stirred for 15 min. 2-(3-Hydroxypropylamino)pyridine N-oxide (168mg, 1 mmol) was added. The reaction was stirred at room temperature for18 h and concentrated. The residue was purified by chromatography (onsilica gel, CH₂Cl₂/CH₃OH/NH₄OH-98.5/1/0.5) to afford 127 mg pale brownoil. NMR spectra of the product were consistent for the proposedstructure.Step 7

A mixture of the product of step 6 (127 mg, 0.3 mmol), 10% Pd/C (50 mg,0.04 mmol), cyclohexene (2.0 ml, 17.8 mmol), and 2-propanol (5.0 ml) washeated at reflux for 4 h. The reaction was allowed to cool to roomtemperature. Additional 10% Pd/C (50 mg, 0.04 mmol) was added. After 18h of refluxing, the reaction was cooled to room temperature, filteredthrough a short column of Celite®, and washed with 100 ml of 2-propanol.The filtrate was concentrated to give 85 mg oil. This product was usedwithout further purification. The NMR spectra were consistent for theproposed structure.

Step 8

The product of step 7 (70 mg, 0.19 mmol) was dissolved in 5 ml methanoland 5 ml 1 N sodium hydroxide solution. The reaction was stirred at roomtemperature for 5.5 h, acidified with 2 ml trifluoroacetic acid, andconcentrated. The residue was purified on HPLC using acetonitrilegradient 10-50% in 30 min to yield 82.7 mg of gummy solid.FAB-MS:(MH+)=341.H NMR(CDCl₃) δ 0.82 (m, 1H), 0.89 (m, 1H), 1.31 (m,1H), 1.70 (dt, 1H), 2.19 (p, 2H), 2.35 (s, 3H), 2.50 (m, 2H), 3.53 (m,2H), 4.04 (t, 2H), 6.64 (dd, 1H), 6.71 (m, 2H), 6.85 (t, 1H), 6.96 (d,1H), 7.78 (m, 2H). Anal Calcd. for C₂₀H₂₄N₂O₃ plus 1.25 CF₃COOH: C,55.96; H, 5.27; N, 5.80. Found: C, 56.24; H, 5.36; N, 5.95.

EXAMPLE 92-[3-fluoro-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

Step 1

A solution of triethyl phosphonoacetate (16.8 g, 75 mmol) in 50 ml THFwas added to a mixture of sodium hydride (1.8 g, 75 mmol) in 125 ml THFat 0° C. After 30 min, 3-fluoro-p-anisaldehyde (10.0 g, 64.9 mmol) in 25ml THF was added at 0° C., and the reaction was stirred at roomtemperature for 30 min. The reaction was diluted with ethyl acetate,washed with 1N HCl solution. The aqueous layer was extracted withadditional ethyl acetate. The combined organic layer was washed withH₂O, brine, dried with Na₂SO₄, and concentrated. The residue waspurified by chromatography (on silica gel, ethyl acetate/hexane=1/4) togive a colorless liquid in 12.9 g. NMR spectra of the product wereconsistent for the proposed structure.

Step 2 The product of step 1 (8.4 g, 37.5 mmol) was dissolved in 75 mlTHF. Under N₂ a solution of diisobutylalumium hydride (150 ml, 1 M inTHF) was added at 0° C. over 30 min. The reaction was stirred for 30 minand quenched with 250 ml 1N HCl solution. The mixture was stirred for 15min and filtered through a short column of Celite®. The product wasextracted with ethyl acetate. The aqueous layer was extracted with ethylacetate. The combined organic layer was dried with MgSO₄ andconcentrated. The residue was purified by chromatography (on silica gel,ethyl acetate/hexane=2/3) to give a white solid in 3.32 g. NMR spectraof the product were consistent for the proposed structureStep 3

Under N₂, diethyl zinc solution (75 ml, 75 mmol, 1.0 M in hexane) wasadded dropwise to a solution of diiodomethane (40.2 g, 150 mmol) in 200ml methylene chloride at 0° C. After stirring at 0° C. for 15 min, asolution of the product of step 2 (10.6 g, 58.2 mmol) in 50 ml methylenechloride was added at 0° C. dropwise. The reaction was warmed to 35° C.After 30 min, the reaction was quenched with H₂O at 0° C. and acidifiedwith 1N HCl. The product was extracted with ethyl acetate. The aqueouslayer was extracted with additional ethyl acetate. The combined organiclayer was washed with H₂O, brine, dried with Na₂SO₄, and concentrated.The residue was purified by chromatography (on silica gel, ethylacetate/hexane=2/3) to afford a pale brown oil in 9.6 g. NMR spectra ofthe product were consistent for the proposed structure.

Step 4

Under N₂ DMSO (8.6 g, 110 mmol) in 30 ml methylene cloride was added toa solution of oxalyl chloride (7.0 g, 55.0 mmol) in 30 ml methylenechloride dropwise at −60° C. and stirred for 2 min. A solution of theproduct of step 3 (9.6 g, 48.9 mmol) in 40 ml methylene cloride wasadded at −60° C. and the reaction was stirred for 15 min. Triethyl amine(22.8 g, 225 mmol) was added at −60° C. The reaction was stirred for 15min and allowed to warm to room temperature. The reaction was quenchedwith 50 ml H₂O and the product was extracted with methylene chloride.The organic layer was washed with 1% HCl, 5% Na₂CO₃, brine, dried withNa_(0.2)SO₄, and concentrated. The residue was purified bychromatography (on silica gel, ethyl acetate/hexane=3/7) to afford awhite solid in 7.32 g. NMR spectra of the product were consistent forthe proposed structure.

Step 5

Under N₂ atmosphere, lithium bis(trimethylsilyl) amide solution (50 ml,1.0M in THF) was added to a mixture of methoxy methyltriphenylphosphonium chloride (17.1 g, 37.6 mmol) in 90 ml THF dropwise at 0° C.After 15 min, it was added to a solution of the product of step 4 (7.3g, 37.6 mmol) in 60 ml THF at 0° C. The reaction was stirred for 5 minand quenched with H₂O. The product was extracted with ethyl acetate. Theaqueous layer was extracted with ethyl acetate. The combined organiclayer was washed with H₂O, brine, and then dried with Na_(0.2)SO₄ andconcentrated. The residue was purified by chromatography (on silica gel,ethyl acetate/hexane=1/9) to yield a colorless oil in 5.32 g. It wasdissolved in 150 ml THF and 100 ml 2N HCl solution. The reaction wasstirred at reflux for 15 min. THF was evaporated and the residue wasdiluted with H₂O and ethyl acetate. The aqueous layer was extracted withethyl acetate. The combined organic layer was washed with 5% NaHCO₃solution, brine, and dried with MgSO₄, and concentrated. The residue waspurified by chromatography (on silica gel, ethyl acetate/hexane=1/9) toyield a colorless oil in 4.52 g. NMR spectra of the product wereconsistent for the proposed structure.

Step 6

A solution of silver nitrate (3.26 g, 19.3 mmol) in 6 ml H₂O was addedto a solution of the product of step 5 (2.0 g, 9.6 mmol) in 45 mlethanol. A solution of Sodium hydroxide (1.54 g, 38.4 mmol) in 6 ml H₂Owas added dropwise at room temperature. After 2 h, the reaction wasfiltered through a pad of Celite®. The residue was diluted with H₂O andextracted with ether (3×30 ml). The aqueous layer was acidified withconcentrated HCl and extracted with chloroform. The organic layer wasdried with MgSO₄ and concentrated to give 1.82 g of yellow solid. Thissolid was dissolved in 50 ml ethanol and 25 ml 4N HCl in dioxane. It wasstirred at room temperature for 48 h. Ethanol and dioxane wereevaporated to afford a clean product as a pale brown oil in 2.0 g. NMRspectra of the product were consistent for the proposed structure.

Step 7

The product of step 6 (2.0 g, 8.6 mmol) was dissolved in 15 ml methylenechloride. Under N₂boron tribromide solution (15 ml, 15 mmol, 1M inmethylene chloride) was added to the above solution dropwise at 0° C.The resulting reaction solution was allowed to warm to room temperature.After 30 min, the reaction was carefully quenched with ethanol. Theproduct was extracted with ethyl acetate and washed with 1N HCl. Theorganic layer was washed with 5% NaHCO₃ solution, brine, dried withMgSO₄, and concentrated. The residue was purified by chromatography (onsilica gel, ethyl acetate/hexane=3/7) to give pale brown oil in 1.63 g.NMR spectra of the product were consistent for the proposed structure.

Step 8

A solution of diethyl azodicarboxylate (731 mg, 4.2 mmol) in 5 ml THFwas added to a solution of the product of step 7 (750 mg, 3.4 mmol) andtriphenylphosphine (1.1 g, 4.2 mmol) in 20 ml THF at room temperatureand stirred for 15 min. 2-(3-hydroxypropylamino)pyridine N-oxide (706mg, 4.2 mmol) was added. The reaction was stirred at room temperaturefor 18 h. THF was evaporated and the residue was purified bychromatography (on silica gel, CH₂Cl₂/CH₃OH/NH₄OH-98.5/1/0.5) to yield835 mg pale brown oil. NMR spectra of the product were consistent forthe proposed structure.

Step 9

A mixture of the product of step 8 (835 mg, 2.15 mmol), 10% Pd/C (250mg, 0.24 mmol), cyclohexene (3.0 ml, 29.6 mmol), and 2-propanol (20 ml)was heated at reflux for 4 h. The reaction was allowed to cool to roomtemperature. Additional 10% Pd/C (250 mg, 0.24 mmol) was added. After 4h of refluxing, the reaction was cooled to room temperature, filteredthrough a short column of Celite®, and washed with 2-propanol. Thefiltrate was concentrated. The residue was purified by chromatography(on silica gel, CH₂Cl₂/CH₃OH/NH₄OH=98.5/1/0.5) to give 482 mg colorlessoil. The NMR spectra were consistent for the proposed structure.

Step 10

The product of step 9 (475 mg, 1.28 mmol) was dissolved in 10 mlmethanol and 10 ml 1N sodium hydroxide solution. The reaction wasstirred at room temperature for 18 h and acidified with 2 mltrifluoroacetic acid. Solvents were evaporated. The residue was purifiedon HPLC using acetonitrile gradient 10-50% in 30 min to yield 434 mggummy solid. FAB-MS:(MH+)=345.4.H-NMR(CDCl₃) δ 0.86 (dt, 1H), 0.95 (dt,1H), 1.30 (m, 1H), 1.72 (dt, 1lH), 2.18 (p, 2H), 2.40 (dd, 1H), 2.49(dd, 1H), 3.58 (t, 1H), 4.10 (t, 2H), 6.72 (t, 1H), 6.80-6.90 (m, 3H),6.95 (d, 1H), 7.80 (t, 1H), 7.81 (d, 1H), 9.09 (br, 1H). Anal Calcd. forC₁₉H₂₁N₂O₃F plus 1.5 CF₃COOH: C, 51.27; H, 4.40; N, 5.44. Found: C,51.12; H, 4.40; N, 5.57.

EXAMPLE 102-[2-fluoro-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticAcid

The title compound was prepared according to procedure described for thepreparation of EXAMPLE 12: FAB-MS:(MH+)=345.4. ¹H NMR (DMSO-6d) δ 0.82(dt, 1H), 0.86 (dt, 1H), 1.23 (m, 1H), 1.78 (dt, 1H), 2.04 (p, 2H), 2.31(dd, 1H), 2.37 (dd, 1H), 3.48 (t, 2H), 4.07 (t, 2H), 6.69 (dd, 1H), 6.77(dd, 1H), 6.86 (t, 1H), 6.96 (t, 1H), 7.06 (d, 1H), 7.90 (t, 1H), 7.94(d, 1H), 8.84 (br, 1H). Anal Calcd. for C₁₉H₂₁N₂O₃F plus 1.75 CF₃COOH:C, 49.68; H, 4.22; N, 5.15. Found: C, 49.58; H, 3.96; N, 5.09.

EXAMPLE 112-[4-[2-[6-(methylamino)-2-pyridinyl]ethoxy]phenyl]]cyclopropaneaceticacid

Step 1

A mixture of trans-4-methoxycinnamic acid (50 g, 281 mmol), 5 mlconcentrated H₂SO₄, and 500 ml ethanol was stirred at reflux for 18 h.The cooled reaction was quenched with saturated NaHCO₃ solution. Theproduct was extracted with ether. The organic layer was dried with MgSO₄and concentrated. The residue was solidified at room temperature toyield a pale brown solid in 54.8 g. NMR spectra of the product wereconsistent for the proposed structure.

Step 2

The product of step 1 (20.6 g, 100 mmol) was dissolved in 150 ml THF. Itwas added to a solution of diisobutylalumium hydride (300 ml, 1M in THF)diluted with THF (150 ml) at 0° C. under N₂ over 20 min. After 1 h, thereaction was quenched with 50 ml acetone and 25 ml ethanol. Theresulting mixture was poured into H₂O and acidified with 1N HCl. Theproduct was extracted with ethyl acetate. The organic layer was driedwith MgSO₄, and concentrated to yield an off-white solid in 15.62 g.This product was used without further purification. NMR spectra of theproduct were consistent for the proposed structure.

Step 3

Diethyl zinc solution (100 ml, 100 mmol, 1.0 M in hexane) was added to asolution of diiodomethane (16.1 ml, 200 mmol) in 175 ml dichloromethaneat 0° C. over 15 min. After stirring at 0° C. for 15 min, a solution ofthe product of step 2 (15.6 g, 95 mmol) in 50 ml dichloromethane wasadded dropwise at 0° C. over 15 min. After 15 min, the reaction wasquenched with 200 ml 1N HCl at 5° C. The product was extracted withdichloromethane. The organic layer was dried with MgSO₄ and concentratedto give a golden oil in 16.47 g. NMR spectra of the product wereconsistent for the proposed structure.

Step 4

The product of step 3 (3.5 g, 19.6 mmol) was dissolved in 40 mldichloromethane. 4-methylmorpholine-N-oxide (3.5 g, 30 mmol) and drymolecular sieves (10.0 g, 4A) were added. The resulting mixture wasstirred at room temperature for 15 min. Tetrapropylammonuim perruthenate(0.351 g, 1.0 mmol) was added. The reaction was stirred at roomtemperature for 2.5 h and filtered through a short column of Celite®.The filtrate was concentrated and residue was purified by chromatography(on silica gel, ethyl acetate/hexane=3/7) to afford a golden oil in 1.9g. NMR spectra of the product were consistent for the proposedstructure.

Step 5

Under N₂, lithium bis(trimethylsilyl) amide solution (90 ml, 1.0M inTHF) was added to a mixture of methoxy methyltriphenyl phosphoniumchloride (29.2 g, 85 mmol) in 60 ml THF dropwise at 0° C. After 15 min,it was added to a solution of the product of step 4 (10.0 g, 56.8 mmol)in 30 ml THF was added at 0° C. The reaction was stirred for 5 min andquenched with H₂O. The product was extracted with ethyl acetate. Theaqueous layer was extracted with ethyl acetate. The combined organiclayer was washed with H₂O, brine, dried with Na₂SO₄, and concentrated.The residue was purified by chromatography (on silica gel, ethylacetate/hexane=1/9) to yield a pale brown oil in 8.6 g. It was dissolvedin 125 ml THF and 125 ml 1.5N HCl solution. The resulting solution wasstirred at reflux for 1 h. THF was evaporated and residue was dilutedwith H₂O and ethyl acetate. The aqueous layer was extracted with ethylacetate. The combined organic layer was washed with 5% NaHCO₃ solution,brine, dried with MgSO₄, and concentrated to afford a yellow oil in 7.8g. This product was used without further purification. NMR spectra ofthe product were consistent for the proposed structure.

Step 6

A solution of silver nitrate (13.9 g, 82.0 mmol) in 20 ml H₂O was addedto a solution of the product of step 5 (7.8 g, 41.0 mmol) in 200 mlethanol. A solution of Sodium hydroxide (6.6 g, 164.0 mmol) in 10 ml H₂Owas added dropwise at room temperature. After 2 h, the reaction wasfiltered through a short column of Celite®. The filtrate was dilutedwith H₂O and extracted with ether (3×30 ml). The aqueous layer wasacidified with concentrated HCl and extracted with chloroform. Thechloroform layer was dried with MgSO₄ and concentrated. The residue wasdissolved in 150 ml ethanol and 50 ml 4N HCl in dioxane. The resultingreaction solution was stirred at room temperature for 18 h andconcentrated to afford a brown oil in 7.88 g. This product was usedwithout further purification. NMR spectra of the product were consistentfor the proposed structure.

Step 7

Boron tribromide solution (40 ml, 40 mmol, 1 M in dichloromethane) wasadded to a solution of the product of step 6 (7.8 g, 32.9 mmol) in 50 mldichloromethane dropwise at 0° C. The resulting reaction solution wasallowed to warm to room temperature. After 30 min, the reaction wascarefully quenched with ethanol. The product was extracted with ethylacetate and washed with 1N HCl. The organic layer was further washedwith 5% NaHCO₃ solution, brine, and dried with MgSO₄, and concentrated.The residue was purified by chromatography (on silica gel, ethylacetate/hexane=1/3) to give a pale brown oil in 3.84 g. NMR spectra ofthe product were consistent for the proposed structure.

Step 8

A solution of diethyl azodicarboxylate (348 mg, 2.0 mmol) in 2 ml THFwas added to a solution of the product of step 7 (275 mg, 1.25 mmol) andtriphenylphosphine (525 mg, 2.0 mmol) in 10 ml THF at room temperatureand stirred for 15 min. 6-(methylamino)-2-pyridyl ethanol (304 mg, 2.0mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 3 h. THF was evaporated and the residue was purified bychromatography (on silica gel, ethyl acetate/hexane=1/1) to yield asolid in 500 mg. NMR spectra of the product were consistent for theproposed structure.

Step 9

The product of step 8 (500 mg, 1.4 mmol) was dissolved in 25 ml methanoland 25 ml 1N sodium hydroxide solution. The reaction was stirred at roomtemperature for 18 h, acidified with 4 ml trifluoroacetic acid, andconcentrated. The residue was purified on HPLC using acetonitrilegradient 15-50% in 30 min to yield 200 mg. FAB-MS:(MH+)=327.4.H NMR(CDCl3) δ 0.82 (dt, 1H), 0.94 (dt, 1H), 1.3 (m, 1H), 1.73 (dt, 1lH),2.43 (d, 2H), 2.97 (s, 3H), 3.23 (t, 2H), 4.29 (t, 2H), 6.59 (d, 1H),6.68 (d, 1H), 6.80 (d, 2H), 7.02 (d, 2H), 7.73 (dd, 1H), 9.84 (br, 1H).Anal Calcd. for C₁₉H₂₂N₂O₃ plus 1.45 CF₃COOH: C, 53.49; H, 4.81; N,5.70. Found: 53.64; H, 5.06; N, 5.92.

EXAMPLE 122-[4-[2-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-6-yl)ethoxy]phenyl]-cyclopropaneaceticAcid

Step 12-amino-6-methyl-3-pyridinol

3-Hydroxy-6-methyl-2-nitropyridine (30 g, 194.6 mmol) was hydrogenatedin ethanol solution at 50° C. using H₂ at 5 psi and 20% Pd(OH)₂/Ccatalyst for 1 hour. Upon completion of the reaction, the catalyst wasfiltered off and the filtrate was concentrated under reduced pressure toget the desired product 1 as a brown solid (23.68 g, 98%). NMR data wasconsistent with the proposed structure.

Step 2

6-methyl-2H-pyrido[3,2-b]-1,4-oxazin-3(4h)-one

chloroacetyl chloride (0.37 mL) was added dropwise to a stirred, cooled(0° C.) mixture of 1 (0.500 g), 0.810 g NaHCO₃, and 4 mL 2-butanone in 4mL water. Once the addition was complete, the reaction mixture waswarmed to room temp. and stirred for 30 minutes, then heated to 75° C.for 2 hours. The reaction mixture was cooled to room temp. and the2-butanone was stripped off under reduced pressure. 1 mL water was addedand the solids were filtered off and washed with water to get the crudeproduct. The solid was dissolved in warmed (50° C.) ethyl acetate andfiltered through a small plug of silica gel. The silica gel was washedwith more warm ethyl acetate, combined with the filtrate, andconcentrated under reduced pressure to get the desired product 2 (0.250g, 38%) as a deep orange solid. NMR data was consistent with theproposed structure.

Step 3

Synthesis of 3,4-dihydro-6-methyl-2H-pyrido[3,2-b]-1,4-oxazine

LiAlH₄ (0.289 g) was slowly added to 15 mL dry THF in a round-bottomflask fitted with a stirbar and a condenser. After stirring for 10minutes, a solution of 2 (1.00 g) in 15 mL dry THF was added dropwise.Upon completion of the addition, the reaction mixture was refluxed for16 hours. The reaction was cooled to room temp. and quenched with 1 MNaOH solution until the mixture had become a milky yellow color. Theprecipitate was filtered off and washed 3 times with CH₂Cl₂. Thefiltrate and washings were combined, washed with brine, dried overMgSO₄, and concentrated under reduced pressure to get 3 (0.910 g, 99%)as a pale yellow oil, which solidified on standing. NMR data wasconsistent with the proposed structure.

Step 4

2,3-dihydro-6-methyl-4H-pyrido[3,2-b]-1,4-oxazine-4-carboxylic acid,1,1-dimethylethyl Ester

A solution of 3 (2.96 g), di-tert-butyl dicarbonate (4.302 g) andtriethylamine (2.75 mL) in 35 mL DMF was warmed to 50° C. with stirringfor 16 hours. The reaction mixture was allowed to cool to room temp. andwas concentrated under reduced pressure to get the crude product, whichwas purified by chromatography on silica gel (eluent: 30/70 ethylacetate/hexane). The desired fractions were combined and concentratedunder reduced pressure to get the desired product 4 (1.46 g, 30%) as ayellow oil. NMR data was consistent with the proposed structure.

Step 5

4-[(1,1-dimethylethoxy)carbonyl]-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine-6-aceticAcid, Ethyl Ester

Lithium diisopropylamide solution (8.17 Ml, 2.0 M inTHF/ethylbenzene/heptane) was added dropwise to a chilled (−78° C.),stirred solution of 4 (1.46 g) and diethyl carbonate (2.549 g) in 15 mLdry THF under nitrogen atmosphere. After 30 minutes the reaction wasquenched with saturated NH₄Cl solution and warmed to room temp. Themixture was extracted three times with ethyl acetate and all organicextracts were combined, dried over MgSO₄, and concentrated under reducedpressure to get the crude product, which was purified by chromatographyon silica gel (eluent: 40/60 ethyl acetate/hexane). The desiredfractions were combined and concentrated under reduced pressure to getthe desired product 5 (1.48 g, 78%) as a yellow solid. NMR data wasconsistent with the proposed structure.

Step 6

3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine-6-ethanol

To a solution of 5 (1.48 g) in dry THF (20 mL) at room temp. was added asolution of LiBH₄ (2.0 M in THF, 2.75 mL), and the resulting mixture washeated to reflux. After 16 hours the mixture was cooled to 0° C. andcarefully quenched with water (20 mL). After 10 minutes, the mixture wasextracted three times with ethyl acetate. The combined organic extractswere dried over MgSO₄, filtered, and concentrated under reducedpressure. This residue was dissolved in CH₂Cl₂ (3 mL), and to thissolution was added 4 M HCl in dioxane (6 mL) all at once at room temp.After 4 hours, the mixture was concentrated under reduced pressure toget the crude product, which was chromatographed on silica gel (eluent:94.5/5/0.5 chloroform/ethanol/ammonium hydroxide). The desired fractionswere combined and concentrated under reduced pressure to get the desiredproduct 6 (0.364 g, 44%) as a pale yellow solid. H MNR(CDCl3) δ 2.78 (t,2H), 3.55 (m, 2H), 3.92 (t, 2H), 4.23 (m, 2H), 6.40 (d, 2H), 6.90 (d,2H).

Step 7

2-[4-[2-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-6-yl)ethoxy]phenyl]cyclopropaneaceticAcid, Ethyl Ester

A solution of diethyl azodicarboxylate (348 mg, 2.0 mmol) in 2 ml THFwas added to a solution of the product of step 8, EXAMPLE 11 (366 mg,1.66 mmol) and triphenylphosphine (525 mg, 2.0 mmol) in 10 ml THF atroom temperature and stirred for 15 min. The product of step 6 (360 mg,2.0 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 3 h. THF was evaporated and the residue was purified bychromatography (on silica gel, CH₂Cl₂/CH₃OH/NH₄OH 98.5/1/0.5) to yieldan yellow oil in 380 mg. NMR spectra of the product were consistent forthe proposed structure.

Step 8

2-[4-[2-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-6-yl)ethoxy]phenyl]cyclopropaneaceticAcid

The product of step 7 (380 mg, 1 mmol) was dissolved in 5 ml methanoland 2.5 ml 1N sodium hydroxide solution. The reaction was stirred atroom temperature for 18 h, acidified with 1 ml trifluoroacetic acid, andconcentrated. The residue was purified on HPLC using acetonitrilegradient 15-50% in 30 min to yield 210 mg desired product as an yellowoil. FAB-MS:(MH+)=355.H MNR(CDCl3) δ 0.78 (m, 1H), 0.86 (m, 1H), 1.21(m, 1H), 1.70 (m, 1H), 2.35 (m, 2H), 3.12 (t, 2H), 3.63 (t, 2H), 4.22(t, 2H), 4.26 (t, 2H), 6.65 (d, 1H), 6.79 (d, 2H), 7.0 (d, 2H), 7.6 (d,1H). Anal Calcd. for C₂₀H₂₂N₂O₄ plus 1 CF₃COOH and 0.2H₂O: C, 55.98; H,5.00; N, 5.93. Found: 55.90; H, 5.28; N, 5.24.

EXAMPLE 13 3-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclobutaneaceticAcid

The compounds of Formula 1 containing a cyclobutyl with a1,3-substituion can be synthesized as shown in the above scheme. Forexample, reaction of 4-methoxystyrene with in-situ generateddichloroketene gives the cycloadduct which can be dehalogenated to givethe cyclobutanone derivative shown in Step 2. The reaction described inTetrahedron Asymmetry 10, 2113-2118, 1999 for other substituted styrenescan be used to accomplish their synthesis. Elaboration of thisintermediate involving Horner-Emmons reaction, reduction of olefin,demethylation, Mitsunobu reaction, deoxygenation and hydrolysis of estergives the target compound. The experimental conditions described inSteps 2-7, in Example 2 can be used to achieve the synthesis of targetcompound.

EXAMPLE 14(1-Methyl-2-{4-[3-(pyridin-2-ylamino)-propoxyl]-phenyl}-cyclopropyl)-aceticAcid

The title compound was prepared starting with benzaldehyde andtriethylphosphonopropionoate following the reaction sequence shown inscheme 8. ¹H MNR(CDCl₃) δ 0.83 (t, 1H), 0.86 (s, 3H), 0.93 (dd, 1H),2.05 (dd, 1lH), 2.19 (p, 2H), 2.29 (d, 1H), 2.57 (d, 1H), 2.57 (d, 1H),3.53 (q, 2H), 4.05 (t, 2H), 6.70 (t, 1H), 6.81 (d, 2H), 6.85 (d, 1H),7.15 (d, 2H), 7.73 (ddd, 1H), 7.80 (d, 1H), 9.70 (br, 1H); MS (ESI) m/z=341 (MH+); Anal Calcd. for C₂₀H₂₄N₂O₃.1.65 CF₃COOH: C, 52.95; H, 4.89;N, 5.30. Found: 52.90; H, 4.95; N, 5.36.

EXAMPLE 15(1-Methyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound was prepared starting with benzaldehyde andtriethylphosphonopropionoate following the reaction sequence shown inscheme 8. ¹H MNR(CDCl₃) δ 0.83 (t, 1H), 0.86 (s, 3H), 0.92 (dd, 1H),1.94 (p, 2H), 2.04 (dd, 1lH), 2.29 (d, 1H), 2.55 (d, 1H), 2.76 (t, 2H),3.18 (t, 2H), 3.52 (t, 2H), 4.29 (t, 2H), 6.00 (brs, 2H), 6.53 (d, 1H),6.82 (d, 2H), 7.15 (d, 2H), 7.34 (d, 1H), 9.64 (br, 1H); Anal Calcd. forC₂₂H₂₆N₂O₃.0.1.5 CF₃COOH: C, 56.81; H, 5.50; N, 5.42. Found: 57.13; H,5.50; N, 5.08.

EXAMPLE 16(2-{2-Methoxy-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 11.

EXAMPLE 17[1-Methyl-2-(4-{2-[6-(2,2,2-trifluoro-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 18(2-{4-[2-(6-Ethylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 19[2-(4-{2-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 20[2-(4-{2-[6-(2,2,2-Trifluoro-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 21[2-(4-{2-[6-(3-Methoxy-propylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 22(2-{2-Fluoro-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME11.

EXAMPLE 23(2-{2-Acetoxy-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME11.

EXAMPLE 24(1-Methoxymethyl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 25(1-Methanesulfonylmethyl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 26(1-Pyridin-3-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 27(1-Benzo[1,3]dioxol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 28(1-(2,3-Dihydro-benzofuran-6-yl)-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 29(1-Isoxazol-3-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 30(1-Isoxazol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 31(1-Oxazol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 32(2-{4-[3-(Pyridin-2-ylamino)-propoxy]-phenyl}-1-thiazol-5-yl-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 33(1-Methoxymethyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 34(1-Methanesulfonylmethyl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 35(1-Pyridin-3-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 36(1-(2,3-Dihydro-benzofuran-6-yl)-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 37(1-Benzo[1,3]dioxol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 38(1-Isoxazol-3-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 39(1-Isoxazol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 40(1-Oxazol-5-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 41(2-{4-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-1-thiazol-5-yl-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 8.

EXAMPLE 42(2-{4-[3-(1-H-Imidazol-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 9.

EXAMPLE 43(2-{3-Fluoro-4-[3-(1-H-imidazol-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 9.

EXAMPLE 44(2-{3-Fluoro-4-[3-(3-H-imidazol-4-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 9.

EXAMPLE 45(2-{4-[3-(3-H-imidazol-4-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 9.

EXAMPLE 46(2-{4-[3-(1-H-Pyrazol-3-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 9.

EXAMPLE 47(2-{3-Fluoro-4-[3-(1-H-pyrazol-3-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 9.

EXAMPLE 48(1-Methyl-2-{4-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 49(2-{4-[2-(6-Ethylamino-pyridin-2-yl)-ethoxy]-phenyl}-1-methyl-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 50[2-(4-{2-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-1-methyl-cyclopropyl]-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 51[2-(4-{2-[6-(3-Methoxy-propylamino)-pyridin-2-yl]-ethoxy}-phenyl)-1-methyl-cyclopropyl]-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 52(2-{4-[2-(6-Acetylamino-pyridin-2-yl)-ethoxy]-phenyl}-1-methyl-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

EXAMPLE 53(2-{4-[2-(6-Acetylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticAcid

The title compound is prepared according to the general proceduresdescribed in SCHEME 10.

The activity of the compounds of the present invention was tested in thefollowing assays.

Vitronectin Adhesion Assay

Materials

Human vitronectin receptors α_(V)β₃ and α_(V)β₅ were purified from humanplacenta as previously described [Pytela et al., Methods in Enzymology,144:475-489 (1987)]. Human vitronectin was purified from fresh frozenplasma as previously described [Yatohgo et al., Cell Structure andFunction, 13:281-292 (1988)]. Biotinylated human vitronectin wasprepared by coupling NHS-biotin from Pierce Chemical Company (Rockford,Ill.) to purified vitronectin as previously described [Charo et al., J.Biol. Chem., 266(3):1415-1421 (1991)]. Assay buffer, OPD substratetablets, and RIA grade BSA were obtained from Sigma (St. Louis, Mo.).Anti-biotin antibody was obtained from Sigma (St. Luois, Mo.). NalgeNunc-lmmuno microtiter plates were obtained from Nalge Company(Rochester, N.Y.).

Methods Solid Phase Receptor Assays

This assay was essentially the same as previously reported [Niiya etal., Blood, 70:475-483 (1987)]. The purified human vitronectin receptorsα_(V)β₃ and α_(V)β₅ were diluted from stock solutions to 1.0 μg/mL inTris-buffered saline containing 1.0 mM Ca⁺⁺, Mg⁺⁺, and Mn⁺⁺, pH 7.4(TBS⁺⁺⁺). The diluted receptors were immediately transferred to NalgeNunc-lmmuno microtiter plates at 100 μL/well (100 ng receptor/well). Theplates were sealed and incubated overnight at 4° C. to allow thereceptors to bind to the wells. All remaining steps were at roomtemperature. The assay plates were emptied and 200 μL of 1% RIA gradeBSA in TBS⁺⁺⁺ (TBS⁺⁺⁺/BSA) were added to block exposed plastic surfaces.Following a 2 hour incubation, the assay plates were washed with TBS⁺⁺⁺using a 96 well plate washer. Logarithmic serial dilution of the testcompound and controls were made starting at a stock concentration of 2mM and using 2 nM biotinylated vitronectin in TBS⁺⁺⁺/BSA as the diluent.This premixing of labeled ligand with test (or control) ligand, andsubsequent transfer of 50 μL aliquots to the assay plate was carried outwith a CETUS Propette robot; the final concentration of the labeledligand was 1 nM and the highest concentration of test compound was1.0×10⁻⁴ M. The competition occurred for two hours after which all wellswere washed with a plate washer as before. Affinity purified horseradishperoxidase labeled goat anti-biotin antibody was diluted 1:2000 inTBS⁺⁺⁺/BSA and 125 μL was added to each well. After 45 minutes, theplates were washed and incubated with OPD/H₂O₂ substrate in 100 mM/LCitrate buffer, pH 5.0. The plate was read with a microtiter platereader at a wavelength of 450 nm and when the maximum-binding controlwells reached an absorbance of about 1.0, the final A₄₅₀ were recordedfor analysis. The data were analyzed using a macro written for use withthe EXCEL spreadsheet program. The mean, standard deviation, and %CVwere determined for duplicate concentrations. The mean A₄₅₀ values werenormalized to the mean of four maximum-binding controls (no competitoradded)(B-MAX). The normalized values were subjected to a four parametercurve fit algorithm [Rodbard et al., Int. Atomic Energy Agency, Vienna,pp 469 (1977)], plotted on a semi-log scale, and the computedconcentration corresponding to inhibition of 50% of the maximum bindingof 2 biotinylated vitronectin (IC₅₀) and corresponding R² was reportedfor those compounds exhibiting greater than 50% inhibition at thehighest concentration tested; otherwise the IC₅₀ is reported as beinggreater than the highest concentration tested.β-[2-[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxoethyl]amino]-3-pyridinepropanoicacid [U.S. Pat. No. 5,602,155 Example 1] which is a potent α_(V)β₃antagonist (IC₅₀ in the range 3-10 nM) was included on each plate as apositive control.

PURIFIED IIb/IIIa RECEPTOR ASSAY

Materials

Human fibrinogen receptor (IIb/IIIa) was purified from outdatedplatelets. (Pytela, R., Pierschbacher, M. D., Argraves, S., Suzuki, S.,and Rouslahti, E. “Arginine-Glycine-Aspartic acid adhesion receptors”,Methods in Enzymology 144(1987):475-489.) Human vitronectin was purifiedfrom fresh frozen plasma as described in Yatohgo, T., Izumi, M.,Kashiwagi, H., and Hayashi, M., “Novel purification of vitronectin fromhuman plasma by heparin affinity chromatography,” Cell Structure andFunction 13(1988):281-292. Biotinylated human vitronectin was preparedby coupling NHS-biotin from Pierce Chemical Company (Rockford, Ill.) topurified vitronectin as previously described. (Charo, I. F., Nannizzi,L., Phillips, D. R., Hsu, M. A., Scarborough, R. M., “Inhibition offibrinogen binding to GP IIb/IIIa by a GP IIIa peptide”, J. Biol. Chem.266(3)(1991): 1415-1421.) Assay buffer, OPD substrate tablets, and RIAgrade BSA were obtained from Sigma (St. Louis, Mo.). Anti-biotinantibody was obtained from Sigma (St. Louis, Mo.). Nalge Nunc-immunomicrotiter plates were obtained from (Rochester, N.Y.). ADP reagent wasobtained from Sigma (St. Louis, Mo.).

Methods

Solid Phase Receptor Assays

This assay is essentially the same reported in Niiya, K., Hodson, E.,Bader, R., Byers-Ward, V. Koziol, J. A., Plow, E. F. and Ruggeri, Z. M.,“Increased surface expression of the membrane glycoprotein IIb/IIIacomplex induced by platelet activation: Relationships to the binding offibrinogen and platelet aggregation”, Blood 70(1987):475-483. Thepurified human fibrinogen receptor (IIb/IIIa) was diluted from stocksolutions to 1.0 μg/mL in Tris-buffered saline containing 1.0 mM Ca⁺⁺,Mg⁺⁺, and Mn⁺⁺, pH 7.4 (TBS⁺⁺⁺). The diluted receptor was immediatelytransferred to Nalge Nunc-Immuno microtiter plates at 100 μL/well (100ng receptor/well). The plates were sealed and incubated overnight at 4°C. to allow the receptors to bind to the wells. All remaining steps wereat room temperature. The assay plates were emptied and 200 μL of 1% RIAgrade BSA in TBS⁺⁺⁺ (TBS⁺⁺⁺/BSA) were added to block exposed plasticsurfaces. Following a 2 hour incubation, the assay plates were washedwith TBS⁺⁺⁺ using a 96 well plate washer. Logarithmic serial dilution ofthe test compound and controls were made starting at a stockconcentration of 2 mM and using 2 nM biotinylated vitronectin inTBS⁺⁺⁺/BSA as the diluent. This premixing of labeled ligand with test(or control) ligand, and subsequent transfer of 50 μL aliquots to theassay plate was carried out with a CETUS Propette robot; the finalconcentration of the labeled ligand was 1 nM and the highestconcentration of test compound was 1.0×10⁻⁴ M. The competition occurredfor two hours after which all wells were washed with a plate washer asbefore. Affinity purified horseradish peroxidase labeled goatanti-biotin antibody was diluted 1:2000 in TBS⁺⁺⁺/BSA and 125 μL wereadded to each well. After 45 minutes, the plates were washed andincubated with ODD/H₂O₂ substrate in 100 mM/L citrate buffer, pH 5.0.The plate was read with a microtiter plate reader at a wavelength of 450nm and when the maximum-binding control wells reached an absorbance ofabout 1.0, the final A₄₅₀ were recorded for analysis. The data wereanalyzed using a macro written for use with the EXCELJ spreadsheetprogram. The mean, standard deviation, and %CV were determined forduplicate concentrations. The mean A₄₅₀ values were normalized to themean of four maximum-binding controls (no competitor added)(B-MAX). Thenormalized values were subjected to a four parameter curve fitalgorithm, [Robard et al., Int. Atomic Energy Agency Vienna, pp 469(1977)], plotted on a semi-log scale, and the computed concentrationcorresponding to inhibition of 50% of the maximum binding ofbiotinylated vitronectin (IC₅₀) and corresponding R² was reported forthose compounds exhibiting greater than 50% inhibition at the highestconcentration tested; otherwise the IC₅₀ is reported as being greaterthan the highest concentration tested.β-[2-[5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-1-oxoethyl]amino]-3-pyridinepropanoicacid [U.S. Pat. No. 5,602,155 Example 1] which is a potent α_(V)β₃antagonist (IC₅₀ in the range 3-10 nM) was included on each plate as apositive control.

Human Platelet Rich Plasma Assays

Healthy aspirin free donors were selected from a pool of volunteers. Theharvesting of platelet rich plasma and subsequent ADP induced plateletaggregation assays were performed as described in Zucker, M. B.,“Platelet Aggregation Measured by the Photometric Method”, Methods inEnzymology 169(1989):117-133. Standard venipuncture techniques using abutterfly allowed the withdrawal of 45 mL of whole blood into a 60 mLsyringe containing 5 mL of 3.8% trisodium citrate. Following thoroughmixing in the syringe, the anti-coagulated whole blood was transferredto a 50 mL conical polyethylene tube. The blood was centrifuged at roomtemperature for 12 minutes at 200× g to sediment non-platelet cells.Platelet rich plasma was removed to a polyethylene tube and stored atroom temperature until used. Platelet poor plasma was obtained from asecond centrifugation of the remaining blood at 2000× g for 15 minutes.Platelet counts are typically 300,000 to 500,000 per microliter.Platelet rich plasma (0.45 mL) was aliquoted into siliconized cuvettesand stirred (1100 rpm) at 37° C. for 1 minute prior to adding 50 uL ofpre-diluted test compound. After 1 minute of mixing, aggregation wasinitiated by the addition of 50 uL of 200 uM ADP. Aggregation wasrecorded for 3 minutes in a Payton dual channel aggregometer (PaytonScientific, Buffalo, N.Y.). The percent inhibition of maximal response(saline control) for a series of test compound dilutions was used todetermine a dose response curve. All compounds were tested in duplicateand the concentration of half-maximal inhibition (IC₅₀) was calculatedgraphically from the dose response curve for those compounds whichexhibited 50% or greater inhibition at the highest concentration tested;otherwise, the IC₅₀ is reported as being greater than the highestconcentration tested.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

is a 4-8 membered monocyclic ring or 7-12 membered bicyclic ring; whichring is optionally saturated or unsaturated, which ring is optionallysubstituted with one or more substituent selected from the groupconsisting of alkyl, haloalkyl, aryl, heteroaryl, halogen, alkoxyalkyl,aminoalkyl, hydroxy, nitro, alkoxy, hydroxyalkyl, thioalkyl, amino,alkylamino, arylamino, alkylsulfonamide, acyl, acylamino, alkylsulfone,sulfonamide, allyl, alkenyl, methylenedioxy, ethylenedioxy, alkynyl,carboxamide, cyano, and —(CH₂)_(m) COR; m is 0 to 2; R is hydroxy,alkoxy, alkyl or amino; A¹ is a pyridinyl of the formula

optionally substituted by one or more R^(k) selected from the groupconsisting of hydroxy, alkyl, alkoxy, alkoxyalkyl, thioalkyl, haloalkyl,cyano, amino, alkylamino, halogen, acylamino, sulfonamide and —COR; R ishydroxy, alkoxy, alkyl or amino; with respect to z¹ and Z²: Z¹ isselected from the group consisting of CH₂, O, N, CO, S, SO, SO₂,

and NRk; R_(k) is selected from H or lower alkyl; Z² is a 2 to 5 carbonlinker optionally containing one or more heteroatom selected from thegroup consisting of O, S and N; or Z¹-Z² contains a moiety selected fromthe group consisting of carboxamide, sulfone, sulfonamide, alkenylene,alkynylene, and acyl; wherein the carbon and nitrogen atoms of Z¹-Z² areoptionally substituted by alkyl, alkoxy, thioalkyl, alkylsulfone, aryl,alkoxyalkyl, hydroxy, alkylamino, heteroaryl, alkenyl, alkynyl,carboxyalkyl, halogen, haloalkyl or acylamino; wherein Z²-Z¹ is attachedto

at the para or meta position relative to the X substituent; n is 0 to 2;R^(c) is selected from the group consisting of hydrogen; alkyl; halogen,hydroxy, nitro, alkoxy, amino, haloalkyl, aryl, heteroaryl, alkoxyalkyl,aminoalkyl, hydroxyalkyl, thioalkyl, alkylamino, arylamino,alkylsulfonylamino, acyl, acylamino, sulfonyl, sulfonamide, allyl,alkenyl, methylenedioxy, ethylenedioxy, alkynyl, alkynylalkyl, carboxy,alkoxycarbonyl, carboxamido, cyano, and —(CH₂), COR; X¹ is selected fromthe group consisting of —O—, CO, SO₂, NR and (CHR^(p))_(q); R^(m) is Hor alkyl; R^(p) is H, alkyl; alkoxy or hydroxy; q is 0 or 1; withrespect to X, X² and Y: X² is selected from the group consisting of—CHW—, CO, SO₂, O, NR^(f) and S; R^(f) is H or alkyl; R^(e) is selectedfrom the group consisting of H, alkyl, hydroxy and alkoxy; X or Y areindependently selected from the group consisting of —CR⁸— or —N— whereinR^(g) is selected from the group consisting of H, alkyl, haloalkyl,fluoro, alkoxyalkyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,alkylsulfone, hydroxyalkyl, hydroxy, alkoxy, and carboxyalkyl; or thegroup X—X₂—Y contains a moiety selected from the group consisting ofacyl, alkyl, amino, ether, thioether, sulfone and olefin;

forms a cycloalkyl, optionally substituted with one or more substituentselected from the group consisting of alkyl, halogen, cyano,carboalkoxy, haloalkyl, alkoxyalkyl, alkylsulfone, aryl, heteroaryl,aralkyl, heteroaralkyl, or alkoxy; and R^(b) is X₃- R^(h) wherein X₃ isselected from the group consisting of O, S and NR¹ wherein R^(h) andR^(j) are independently selected from the group consisting of H, alkyl,acyl, aryl, aralkyl and alkoxyalkyl.
 2. A compound according to claim 1wherein A¹ is selected from the group consisting of

 Z^(a) is selected from the group, consisting of H, alkyl, alkoxy,hydroxy, amine alkylamine, dialkylamine, carboxyl, alkoxycarbonyl,hydroxyalkyl, halogen and haloalkyl; and R¹ is selected from the groupconsisting of H, alkyl, alkoxyalkyl, acyl, haloalkyl, alkoxycarbonyl,pyridylamino, imidazolylamino, morpholinopyridine,tetrahydronaphthyridine, oxazolylamino, thiazolylamino,pyrimidinylamino, quinoline, isoquinoline, tetrahydroquinoline,imidazopyridine, benzimidazole, pyridone, and quinolone.
 3. A compoundaccording to claim 1 wherein A¹ is selected from the group consisting of

 X⁴ is selected from the group consisting of H, alkyl, branched alkyl,alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino,alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano and acylamino; X⁵ isselected from the group consisting of H, alkyl, branched alkyl,alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino,alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano and acylamino; X⁶ isselected from the group consisting of H, alkyl, halogen, alkoxy,hydroxy, and haloalkyl; and R⁷⁹ is selected from the group consisting ofhydroxy, alkoxy, alkyl and amino.
 4. A compound according to the whereinthe moiety A¹-Z² is selected from the group consisting of

 X⁴ is selected from the group consisting of H; alkyl, branched alkyl,alkylamino, alkoxyalkylamino, haloalkyl, thioalkyl, halogen, amino,alkoxy, aryloxy, alkoxyalkyl, hydroxy, cyano and acylamino; R⁸⁰ isselected from the group consisting of hydroxy, alkoxy, alkyl and amino;R⁸¹ is selected from the group consisting of hydroxy, alkoxy, alkyl andamino; and R⁸² is selected from the group consisting of hydroxy, alkoxy,alkyl and amino.
 5. A compound according to claim 1 wherein X₁ is(CHR^(p))_(q); wherein q=0; B is a 3-, 4-, or a 5-membered cycloalkylobtained by combining X—X₂—Y; A is a phenyl ring substituted with R^(c);and n=1.
 6. A compound according to claim 5,

wherein the ring B is a cyclopropyl; Y=CR^(g); wherein R^(g) is selectedfrom the group consisting of H, alkyl, haloalkyl, alkoxyalkyl, alkynyl,aryl, heteroaryl, aralkyl, heteroaralkyl, alkylsulfone, hydroxyalkyl,hydroxy, alkoxy, and carboxyalkyl; A is a phenyl ring substituted withR^(c); and R^(b)=OH.
 7. A compound according to claim 6 wherein R^(g) isselected from the group consisting of

R⁸³ is selected from the group consisting of H, alkyl, OMe, OH, andhalogen; X⁷ is selected from the group consisting of CH2 and O; R⁸⁴ isselected from the group consisting of H, alkyl, OMe, OH, and halogen;R⁸⁵ is selected from the group consisting of H, alkyl, OMe, OH, andhalogen; X⁸ is selected from the group consisting of NH, NMe, O, and S;R⁸⁶ is selected from the group consisting of H and Me; R⁸⁷ is selectedfrom the group consisting of H and Me; R⁸⁸ is selected from the groupconsisting of H, alkyl, OMe, OH, and halogen; R⁸⁹ is selected from thegroup consisting of H and Me; B¹ is selected from the group consistingof O, SO2, S and CO; R⁹⁰ is selected from the group consisting of alkyland aryl; R⁹¹ is selected from the group consisting of alkyl and aryl;and R⁹² is selected from the group consisting of aryl and heteroaryl. 8.A compound according to claim 6 wherein A¹ is selected from the groupconsisting of

 X⁹ is selected from the group consisting of H, alkyl, and acyl; R⁹³ isselected from the group consisting of H, Me, OH and alkoxyalkyl; and R⁹³is selected from the group consisting of H, Me, OMe, and OH.
 9. Acompound according to claim 6 wherein ring A is a phenyl ring; and Z₁₋Z₂and X₁-X are connected para to each other.
 10. A compound according toclaim 9 wherein the phenyl ring is optionally substituted with one ormore substituents selected from the group consisting of alkyl; halogen,hydroxy, alkoxy, haloalkyl, aryl, heteroaryl, alkoxyalkyl, sulfonamide,methylenedioxy, ethylenedioxy, alkynyl, and alkynylalkyl.
 11. A compoundaccording to claim 9 wherein Z is selected from the group consisting ofCH₂, O, NR₂, CO, S, SO, and SO₂.
 12. A compound according to claim 9wherein A¹ is selected from the group consisting of


13. A compound according to the claim 1,

wherein X¹ is (CHR^(p))_(q); wherein q=o; A is a phenyl ring substitutedwith R^(c) B is a cyclopropyl obtained by combining X—X₂—Y; n=1; andR_(m) and R_(n) are selected from the group consisting of H, alkyl,halogen, alkoxy, haloalkyl, alkoxyalkyl, alkylsulfone, cyano,carboalkoxy, aryl, heteroaryl, aralkyl and heteroaralkyl; or R_(m) andR_(n) form a spirocyclic ring system.
 14. A compound according to theclaim 13 wherein A¹ is selected from the group consisting of

 R⁹⁴ is selected from the group consisting of H, Me, OH, andalkoxyalkyl; R⁹⁴ is selected from the group consisting of H, Me, OMe,and OH; and X⁹ is selected from the group consisting of H, alkyl, andacyl.
 15. A compound according to claim 1 selected from the groupconsisting of:2-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneacetic acid;2-[4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopentaneacetic acid;3-[4-3-(2-pyridinylamino)propoxy]phenyl]cyclopentaneacetic acid;2,2-difluoro-3-[4-[3(2-pyridinylamino)propoxy]phenyl)cyclopropane-aceticacid(2-(4-[2-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl)-cyclopropyl)-aceticacid; 2-[3-methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneacetic acid;2-(2-methoxy-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropane-aceticacid;2-[2-methyl-4-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropane-aceticacid;2-[3-fluoroa-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid;2-[2-fluoroa-[3-(2-pyridinylamino)propoxy]phenyl]cyclopropaneaceticacid;2-[4-[2-[6-(methylamino)-2-pyridinyl]ethoxy]phenyl]cyclopropane-aceticacid;2-[4-[2-(3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazin-6-yl)ethoxy]phenyl)-cyclopropaneaceticacid; 3-(4-[3-(2-pyridinylamino)propoxy]phenyl]cyclobutaneacetic acid;(2-{2-Methoxy-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid;(2-{2-Fluoro-4-[3-(pyridin-2-ylamino)-propoxy]-phenyl)-cyclopropyl)-aceticacid;(2-{2-Acetoxy4-[3-(pyridin-2-ylamino)-propoxy]-phenyl)-cyclopropyl)-aceticacid; (1-Methyl-2-14-[3-(pyridin-2-ylamino)-propoxy]-phenyl)-cyclopropyl)-acetic acid;(1-Methoxymethyl-2-(4-[3-(pyridin-2-ylamino)-propoxy]-phenyl)-cyclopropyl)-aceticAcid;(1-Methanesulfonylmethyl-2-{4-(3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid; (1-Pyridin-3-yl-2-(4-[3-(pyridin-2-ylamino)-propoxy]-phenyl)-cyclopropyl)-acetic acid;(1-Benzo[1-3]dioxole-5-yl-2-{4-[-3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid;(1-(2-3-Dihydro-benzofuran-6-yl)-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid;(1-isoxazol-3-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid;(1-isoxazol-5-yl-2-{4-[3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid;(1-oxazol-5-yl-2-{4-(3-(pyridin-2-ylamino)-propoxy]-phenyl}-cyclopropyl)-aceticacid;(2-{4-[3-(Pyridin-2-ylamino)-propoxy]-phenyl}-1-thiazol-5-yl-cyclopropyl)-aceticacid;(1-Pyridin-3-yl-2-{4-[2-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid;(1-Methyl-2-{4-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid;(2-{4-[2-(6-Ethylamino-pyridin-2-yl)-ethoxy]-phenyl}-1-methyl-cyclopropyl)-aceticacid; [2-(4-(2-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]-ethoxy1-phenyl)-1-methyl-cyclopropyl]-acetic acid;[2-(4-{2-(6-(3-Methoxy-propylamino)-pyridin-2-yl]-ethoxy}-phenyl)-1-methyl-cyclopropyl]-aceticacid; (2-{4-[2-(6-Acetylamino-pyridin-2-yl)-ethoxy]-phenyl}-1-methyl-cyclopropyl)-aceticacid;[1-Methyl-2-(4-{2-(6-(2,2,2-trifluoro-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticacid;(2-{4-[2-[6-Ethylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid;[2-(4-{2-[6-(2-Methoxy-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl-aceticacid;[2-(4-{2-[6-(2,2,2-Trifluoro-ethylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticacid;[2-(4-{2-(6-(3-Methoxy-propylamino)-pyridin-2-yl]-ethoxy}-phenyl)-cyclopropyl]-aceticacid; and(2-{4-[2-(6-Acetylamino-pyridin-2-yl)-ethoxy]-phenyl}-cyclopropyl)-aceticacid.
 16. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 17. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 5 and apharmaceutically acceptable carrier.
 18. A method for treatingconditions mediated by the α_(v)β₃ integrin in a mammal in need of suchtreatment comprising administering an effective α_(v)β₃ inhibitingamount of a compound of claim
 16. 19. A method for treating conditionsmediated by the α_(v)β₃ integrin in a mammal in need of such treatmentcomprising administering an effective α_(v)β₃ inhibiting amount of acompound of claim
 5. 20. The method according to claim 18 wherein thecondition treated is tumor metastasis.
 21. The method according to claim19 wherein the condition treated is tumor metastasis.
 22. The methodaccording to claim 18 wherein the condition treated is solid tumorgrowth.
 23. The method according to claim 19 wherein the conditiontreated is solid tumor growth.
 24. The method according to claim 18wherein the condition treated is angiogenesis.
 25. The method accordingto claim 19 wherein the condition treated is angiogenesis.
 26. Themethod according to claim 18 wherein the condition treated isosteoporosis.
 27. The method according to claim 19 wherein the conditiontreated is osteoporosis.
 28. The method according to claim 18 whereinthe condition treated is humoral hypercalcemia of malignancy.
 29. Themethod according to claim 19 wherein the condition treated is humoralhypercalcemia of malignancy.
 30. The method according to claim 18wherein the condition treated is smooth muscle cell migration.
 31. Themethod according to claim 19 wherein the condition treated is smoothmuscle cell migration.
 32. The method according to claim 18 whereinrestenosis is inhibited.
 33. The method according to claim 19 whereinrestenosis is inhibited.
 34. The method according to claim 18 whereinatheroscelorosis is inhibited.
 35. The method according to claim 19wherein atheroscelorosis is inhibited.
 36. The method according to claim18 wherein macular degeneration is inhibited.
 37. The method accordingto claim 19 wherein macular degeneration is inhibited.
 38. The methodaccording to claim 18 wherein retinopathy is inhibited.
 39. The methodaccording to claim 19 wherein retinopathy is inhibited.
 40. The methodaccording to claim 18 wherein arthritis is inhibited.
 41. The methodaccording to claim 19 wherein arthritis is inhibited.
 42. A method fortreating conditions mediated by the α_(v)β₃ α_(v)β₅ integrin in a mammalin need of such treatment comprising administering an effective α_(v)β₅inhibiting amount of a compound of claim
 1. 43. A method for treatingconditions mediated by the α_(v)β₅ integrin in a mammal in need of suchtreatment comprising administering an effective intearin inhibitingamount of a compound of claim
 1. 44. The method according to claim 42wherein the condition treated is α_(v)β₅ integrin mediated-tumormetastasis.
 45. The method according to claim 43 wherein the conditiontreated is α_(v)β₅ integrin mediated-tumor metastasis.
 46. The methodaccording to claim 42 wherein the condition treated is α_(v)β₅ integrinmediated-solid tumor growth.
 47. The method according to claim 43wherein the condition treated is α_(v)β₅ integrin mediated-solid tumorgrowth.
 48. The method according to claim 42 wherein the conditiontreated is angiogenesis.
 49. The method according to claim 43 whereinthe condition treated is angiogenesis.
 50. The method according to claim42 wherein the condition treated is osteoporosis.
 51. The methodaccording to claim 43 wherein the condition treated is osteoporosis. 52.The method according to claim 42 wherein the condition treated ishumoral hypercalcemia of malignancy.
 53. The method according to claim43 wherein the condition treated is humoral hypercalcemia of malignancy.54. The method according to claim 42 wherein the condition treated issmooth muscle cell migration.
 55. The method according to claim 43wherein the condition treated is smooth muscle cell migration.
 56. Themethod according to claim 42 wherein restenosis is inhibited.
 57. Themethod according to claim 43 wherein restenosis is inhibited.
 58. Themethod according to claim 42 wherein atheroscelorosis is inhibited. 59.The method according to claim 43 wherein atheroscelorosis is inhibited.60. The method according to claim 42 wherein macular degeneration isinhibited.
 61. The method according to claim 43 wherein maculardegeneration is inhibited.
 62. The method according to claim 42 whereinretinopathy is inhibited.
 63. The method according to claim 43 whereinretinopathy is inhibited.
 64. The method according to claim 42 whereinarthritis is inhibited.
 65. The method according to claim 43 whereinarthritis is inhibited.